Thenyldiamine H1-Antihistamine Action,Drug Action

Thenyldiamine is an ethylenediamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


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Propiomazine H1-Antihistamine Action,Drug Action

Propiomazine is a phenothiazine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism. (Wikipedia) Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor. Newly synthesized cardiolipins undergo remodeling, a process carried out by the enzyme tafazzin. A mutated tafazzin gene disrupts this post-synthetic remodeling and causes Barth syndrome (BTHS), an X-linked human disease (PMID: 16973164). BTHS patients seem to lack acyl specificity and consequently, many potential cardiolipin species can exist (PMID: 16226238).


Clocinizine H1-Antihistamine Action,Drug Action

Clocinizine is a first-generation diphenylmethylpiperazine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Homochlorcyclizine H1-Antihistamine Action,Drug Action

Homochlorcyclizine is a diphenylmethylpiperazine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Temelastine H1-Antihistamine Action,Drug Action

Temelastine is a second-generation H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Alcaftadine H1-Antihistamine Action,Drug Action

Alcaftadine is a second-generation piperidine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Bamipine H1-Antihistamine Action,Drug Action

Bamipine is a first-generation piperidine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Deptropine H1-Antihistamine Action,Drug Action

Deptropine is a tricyclic H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Quetiapine H1-Antihistamine Action,Drug Action

Quetiapine is a tricyclic H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Mirtazapine H1-Antihistamine Action,Drug Action

Mirtazapine is a tetracyclic H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Pimethixene H1-Antihistamine Action,Drug Action

Pimethixene is a thioxanthene H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Pyrrobutamine H1-Antihistamine Action,Drug Action

Pyrrobutamine is an H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Thenalidine H1-Antihistamine Action,Drug Action

Thenalidine is a piperidine H1-antihistamine that was withdrawn from Canadian, US, and UK markets in 1963 due to concerns involving neutropenia (DB04826). H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


Tritoqualine H1-Antihistamine Action,Drug Action

Tritoqualine is an H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.


De Novo Triacylglycerol Biosynthesis TG(a-21:0/10:0/a-17:0),Metabolic

A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other animals, as well as vegetable fat. They are also present in the blood to enable the bidirectional transference of adipose fat and blood glucose from the liver, and are a major component of human skin oils. (Wikipedia) De novo biosynthesis of triglycerides is also known as the phosphatidic acid pathway, and it is mainly associated with the liver and adipose tissue. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). The next three steps are localized to the endoplasmic reticulum membrane. The enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. Next, magnesium-dependent phosphatidate phosphatase catalyzes the conversion of phosphatidic acid into diacylglycerol. Last, the enzyme diacylglycerol O-acyltransferase synthesizes triacylglycerol from diacylglycerol and a fatty acyl-CoA.


Histamine H1 Receptor Activation,Signaling

Histamine is a ubiquitous messenger molecule released from mast cells, basophils, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3, and H4. Histamine receptor H1 belongs to the family of G-protein-coupled receptors (GPCRs), and it is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. It is linked to an intracellular G-protein (Gαq) that activates phospholipase C and the phosphatidylinositol (PIP2) signalling pathway which promotes inflammatory processes through calcium ion release and expression of the NF-κB immune response transcription factor. H1-antihistamines inactivate the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Upon binding by histamine, the H1 receptor allosterically activates the G-protein by exchanging GDP for GTP at the G-protein's alpha subunit (Gαq). This results in the dissociation of a Gαq-GTP monomer and a Gβγ dimer from the receptor (Wikipedia). Gαq-GTP activates phospholipase C-beta which cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the secondary messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses through the cytoplasm to the ER and binds to the inositol 1,4,5-trisphosphate (Ins3P) receptor, releasing calcium from the endoplasmic reticulum into the cytoplasm. An increase in the calcium concentration results in increased mediator release and decreased mast cell stability. Both calcium and DAG activate the kinase activity of protein kinase C beta (PKC). Among many other functions, PKC activates NF-κB. This leads to increased antigen presentation and increased expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors.


Lysophosphatidic Acid LPA1 Signalling,Protein

Lysophosphatidic acid (LPA) is a water-soluble phospholipid derivative and a potent signalling molecule that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. All six receptors belong to the G protein-coupled receptor (GPCR) superfamily which initiates intracellular signalling cascades via four G protein classes differentiated by their α subunit type: Gαs, Gαi/o, Gαq/11, Gα12/13. GPCRs mediate a wide range of biological processes, including cell survival, proliferation, migration, and differentiation, vascular regulation, and cytokine release. Due to LPA's physiological importance, abnormal LPA signalling likely contributes to the pathophysiology of many diseases. LPA biosynthesis proceeds through two major pathways: (1) the conversion of lysophospholipids (e.g. LPC, LPE, LPS) into LPA via autotaxin (ATX/Enpp2) and (2) the conversion of phosphatidic acid (PA) into LPA via phospholipase A1 or A2 (PLA1/PLA2). The binding of LPA to an LPAR allosterically activates the heterotrimeric G protein by exchanging GDP for GTP at the G protein's alpha subunit. This results in the dissociation of a Gα-GTP monomer and a Gβγ dimer from the receptor which allows both complexes to begin signalling cascades via downstream effectors. LPA1 signalling has been implicated in important processes such as cell survival, proliferation, adhesion, migration, immune function, and myelination. This receptor can couple with the G proteins Gαi/o, Gαq/11, and Gα12/13. The Gαi/o subunit inhibits the enzyme adenylyl cyclase (AC) which catalyzes the production of the important secondary messenger 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP). Other downstream effectors of Gαi/o include the MAPK/ERK pathway, the PI3K/Akt pathway, and P13K/Rac signalling. The Gαq/11 subunit activates phospholipase C (PLC) which cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the secondary messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses through the cytoplasm to the ER and binds to the inositol 1,4,5-trisphosphate (Ins3P) receptor, releasing calcium from the endoplasmic reticulum into the cytoplasm. Both calcium and DAG activate the kinase activity of protein kinase C beta (PKC). Among many other functions, PKC activates NF-κB. This leads to increased antigen presentation and increased expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. The Gα12/13 subunit regulates cell motility and cytoskeletal remodelling by activating the Rho/ROCK and Rho/SRF pathways.


Lysophosphatidic Acid LPA2 Signalling,Protein


Lysophosphatidic Acid LPA3 Signalling,Protein


Lysophosphatidic Acid LPA4 Signalling,Protein


Lysophosphatidic Acid LPA5 Signalling,Protein


Lysophosphatidic Acid LPA6 Signalling,Protein


Ahr Signal Transduction Pathway,Protein

The aryl hydrocarbon receptor, known as AHR, is a normally cytosolic transcription factor that can bind to foreign compounds such as flavonoids and indoles from foods, as well as synthetic ligands including polychlorobiphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD). This includes 2,3,7,8-tetrachlorodibenzodioxin (TCDD), which is the ligand shown in this pathway.AHR interacts with heat shock protein 90 (HSP90AA1), which acts as a chaperone for it. After this association, the ligand, in this case TCDD, can form a covalent bond with the complex in the cell's cytoplasm. This binding causes AHR and the rest of the complex to translocate into the nucleus of the cell. Once in the nucleus, the heat shock protein dissociates, leaving binding sites which the AHR nuclear translocator (ARNT) then binds to. Finally, the AHR/ARNT complex can interact, either directly or indirectly, with the DNA, in this case specifically a dioxin response element. With other ligands, the complex will bind to the equivalent DNA that corresponds to the genes that allow metabolism of the ligand.


Apoptotic DNA Fragmentation and Tissue Homeostasis,Protein

Apoptotic endonucleases degrade chromosomal DNA during programmed cell death. ICAD and CAD exist in the nucleus in normal cells and is a major endonuclease in apoptosis. Its activation is normally caspase dependent. EndoG resides in mitochondria in normal cells and travels to the nucleus, where it fragments chromosomal DNA upon activation of apoptosis. Once released from the mitochondrial intermembrane space, EndoG activity is caspase independent.


BTG Family Proteins and Cell Cycle Regulation,Protein

BTG Family Member-2 (BTG2) is endowed with antiproliferative activity. The expression of BTG2 in cycling cells induces accumulation of hypophosphorylated, growth-inhibitory forms of Retinoblastoma protein(Rb) and lead to G1 arrest through impairment of DNA synthesis. Rb is a nuclear phosphoprotein whose phosphorylation state oscillates regularly during the cell cycle. Hypophosphorylated Rb associates with members of the E2F family of transcription factors, impairing their activity and leading to a cell cycle block in G1. Conversely, the phosphorylation of Rb inactivates its growth suppression activity by freeing E2F molecules, thus enabling them to transactivate genes required for the progression of the cell into S phase and the remainder of the cell cycle. Cyclin-dependent kinases (CDKs) are the molecules responsible for Rb phosphorylation and its consequent inactivation.


Nitric Oxide Signaling Pathway,Protein

Nitric oxide (NO) is a neurotransmitter that synthesized from L-arginine with faciltation of nitric oxide synthase (NOS). Nitric oxide is essential and required in central nervous system (CNS) and peripheral nervous system (PNS). Nitric oxide has several important functions such as immune responses, blood flow regulation and modulation of neurotransmission. Nitric oxide also participates in controlling sleep, adjusting body temperature, neurosecretion as well as synaptic modulation and plasticity in CNS. While in PNS, nitric oxide participates in visceral smooth muscle relaxation as well as vasodilation mediation.


Ion Channels and Their Functional Role in Vascular Endothelium,Protein

In endothelial cell, ion channels such as agonist-activated nonselective Ca(2+)-permeable cation channels, cyclic nucleotide-activated nonselective cation channels, and store-operated Ca(2+) channels or capacitative Ca(2+) entry are controlled by intracellular Ca(2+) signals. Some of the channels are expressed by trp gene family. Ca(2+) entry is also controlled by large-conductance Ca(2+)-dependent BK(Ca) channels (slo), inwardly rectifying K(+) channels, Ca(2+)-activated Cl(-) channel and volume-regulated anion channel (VRAC). VRAC channels can also transport organic osmolytes and amino acid.


P53 Signaling Pathway,Protein

P53 signaling plays an important role in the co-ordination of the cellular response to different types of stress such as DNA damage and hypoxia. Inactivation of p53 has been implicated in tumor progression, it is thought that more than half of all cancers may involve p53-inactivating mutations. DNA damage, activated oncogenes and oxidative stress can produce stress signals to activate P53 protein, which is a transcriptional activator of p53-regulated genes. Activation of p53-regulated genes will lead to cellular senescence, cell cycle arrest or apoptosis. Activated p53-regulated genes will also communicate with nearby cells for the purpose of DNA repair or feedback loop set-up that can either strengthen or weaken the stress responses of p53 protein.


Phospholipase C Signaling Pathway ,Protein,Phospholipase C pathways is one of the major intracellular signalling pathways regulating hormones. It functions to activate inositol lipid signalling pathways causing the hydrolysis of PIP2 by PLC to IP3 and diacylglycerol to activate protein kinase C. IP3 releases calcium from the endoplasmic reticulum. PIP3 is an important regulator of AKT signaling and downstream pathways.


Ras Signaling Pathway ,Protein

RAS signalling pathway is one of the main pathways to transduce intracellular signals in response to mitogens to controls cell growth, survival and anti-apoptotic programs. RAS proteins are GTP-binding proteins and must be bound to GTP to be active. Active RAS binds and activates effector enzymes that control cell proliferation, survival and other cell behaviours. RAS interacts directly with the catalytic subunit of PI3K to activate lipid kinases controlling the activity of downstream enzymes. Some of these kinases have anti-apoptotic activity, playing an important role in the survival signal of RAS. PI3K is also involved in the regulation of the actin cytoskeleton and transcription factor pathways. RAS also effects exchange factors causing inhibition of transcription factors from FoxO family, part of promoting cell cycle arrest and apoptosis. Normal function of these proteins require post-transcriptional modification. Pathway mutations in activation may result in human tumours.


TNF/Stress Related Signaling,Protein

Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex.  TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of  TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.


Rac 1 Cell Motility Signaling Pathway,Protein

Rac1 is signaling protein part of the Rho GTPase family it is involved in cell motility, cell growth and cytoskeletal reorganization. Rac1 activity is regulated by guanine nucleotide exchange factors (GEFs). GEFs cause the release of GDP, allowing GDP to bind and Rac1 to become activated. GTPase-activated proteins (GAPs) down regulate the activity of GEFs be stimulating the inactivation via binding of GDP to Rac1. Active Rac1 stimulates proteins (ie. Wiskott–Aldrich syndrome) leading to actin polymerization. Actin polymerization is also regulated by cofilin. PAK proteins are critical effectors to cytoskeleton reorganization. PAK1 phosphorylates and activates LIM kinase. LIM kinase then phosphorylates cofilin, inactivating it leading to reduced actin filament severing and depolymerization, therby increasing polymerized actin. Rac1 stimulates lamellipodia and filopodia formation which are involved in cell movement and sensing the environment.  It is proposed that PAK1 is involved in the phosphorylation of myosin light chain affecting myosin light chain phosphorylation.


Cadmium Induces DNA Synthesis and Proliferation in Macrophages ,Protein

Cadmium (Cd(2+)) exposure increases the risk of cancer in humans and animals. Humans may come into contact with cadmium when smoking and ingesting contaminated food. This will increase the risk of lung cancer and prostate cancer. In the millimolar range, cadmium will inhibit cell growth. Cadmium induces DNA synthesis and proliferation and affects signal transduction and mobilization in macrophages. At micromolar concentrations, cadmium significantly increased cell division as judged by thymidine uptake and cell counts. Activating this pathway will increase the availability of the transcription factor NF(kappa)B and will activate the early genes c-fos and c-myc.


Growth Hormone Signaling Pathway ,Protein

Growth hormone is the hormone primarily responsible for body growth. Growth hormone (GH) binds membrane-bound growth hormone receptor (GHR) to activate and enhance the binding of JAK2. This stimulates phosphorylation of JAK2 and GHR. JAK2 initiates GH signal transduction. This activation initiates multiple signalling pathways: STAT transcription factors, activation of kinases, and insulin receptor pathways. GH stimulates Signal Transducer and Activator of Transcription (STAT) and its binding to Sis-inducible elements of the c-fos promoter. C-fos expression has input from multiple pathways. The serum response element binds serum response factors and other complex transcription factors regulated by GH via the MEK/ERK pathway. STAT 5 is also involved in the synthesis of many GH-sensitive genes. STAT proteins are phosphorylated and then released from the GH/JAK2 complex. Once released, they become dimers and move to the nucleus to bind binding sites in GH-regulated genes. STAT proteins may also dimerize with other transcription factors to regulate transcription. GH can stimulate glucose transport in the cell through JAK2 stimulation of IRS proteins that recruit PI3K to regulate glucose transport.


EGF Signalling Pathway,Protein

Epidermal growth factor (EGF) is a potent polypeptide mitogen that initiates its biological activity by interacting with the cell surface. The E G F receptors are both transmembrane proteins with cytosolically exposed tyrosine specific protein kinases which are stimulated by ligand binding. Current data strongly suggests that these kinases are causally linked to many if not all of the biological activities of the EGF receptors. Transmembrane signalling is the result of a composite of ligand-receptor interactions in the endosome (stimulation) and modifications of the primary or quaternary structure of the receptor (activation).


GnRH Signaling Pathway,Protein

Gonadotropin-releasing hormone (GnRH), a hypothalamic neuropeptide, is a main regulator of male and female reproductive function in mammals. GnRH is required for reproduction. GnRH is secreted from the hypothalamus and acts on G-protein coupled receptors in the anterior pituitary. GnRH regulates the production and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) gonadotropins, controlling gametogenesis and steroidogenesis. Activated phospholipase C activates IP3 to release intracellular calcium from the endoplasmic reticulum thereby increasing cytoplasmic calcium. Diacylglycerol is also activated by phospholipase C to stimulate the PKC pathway. The PKC pathway leads to the activation of epidermal growth factor (EGF) receptor and mitogen-activated protein kinases (MAPKs), extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. MAPKs are activated and translocate to the nucleus causing the transcription of gonadotropin genes. GnRH also activates G proteins causing the activation of adenylyl cyclase to generate cAMP. cAMP stimulates PKA to phosphorylate and activate transcription factors that translocate to the nucleus for gene transcription. GnRH also promotes secretion of metalloproteinases (MMPs) which regulate the transcription of gonadotropin subunit genes and the GnRHR gene via autocrine/paracrine mechanisms. PKC induces the release of activated MMPs that mediate transactivation of epidermal growth factor receptor (EGFR) which may result in the modulation of gonadotropin subunit genes.


NF-kB Signaling Pathway,Protein

NF-ÎºB can be found in almost all aminal cell. NF-ÎºB is crucial for cell growth since it can control the cytokine production, DNA transcription as well as cell survival. NF-ÎºB can also response to stress, free radicals, uv irradiation and etc. NF-ÎºB can also response to bacterial and viral antigens; Therefore, it is important for the immune response of infections. Various diseases such as cancer and immune diseases (and more) can be related to inccorect regulation of NF-ÎºB complex. The activation of NF-κB involves two major signalling pathways: the canonical pathways, which responds to diverse stimuli such as ligands of various cytokine receptors, pattern-recognition receptors (PRRs); and noncanonical (or alternative) pathway, which selectively responds to a specific group of stimuli, such as groups of ligands of a subset of TNFR superfamily members (e.g. LTβR, BAFFR, CD40 and RANK). Both pathways are important for regulating immune and inflammatory responses despite their differences in signalling mechanism.


Complement Pathway,Protein

The complement system includes three separate pathways that lead to complement's activation. These pathways all have different molecules that trigger their activation, but all of them lead to a response by phagocytes as part of a response by the innate immune system.In the alternative pathway, complement factor C3 can spontaneously hydrolyze to form a complex with water. Complement factor D is a protease that can work at the same time, and it cleaves complement factor B into factors Ba and Bb. the C3(H2O) complex can bind to factor Bb, which is a C3 convertase, and works to cleave factor C3 into C3a and C3b more quickly. The C3(H2O)Bb complex also binds factor B, leading to easier cleavage into Ba and Bb by factor D. Following this, complement factor C3b can bind to the surface of cells, and on host cells, proteins on the cell membrane can bind to C3b, preventing it from forming complement factor C5 convertase. However, on pathogen cells, these proteins do not exist, complement factor Bb can bind to two molecules of C3b, forming a C5-convertase which is the end point of the other two pathways.In the lectin pathway, mannan-binding lectin serine proteases (MASP) 1 and 2, as well as mannose-binding protein C bind to carbohydrates, specifically mannose, glucose and sugars with specific hydroxide group placements. These sugars are found in the cell walls of bacteria such as salmonella and listeria, as well as some viruses, including HIV-1, and fungal pathogens, such as candida. After the sugar is bound by the proteins, it activates the serine proteases, which then can cleave complement C2 and C4 into C2a, C2b, C4a and C4b respectively. Factors C4b and C2a (sometimes called C2b) can interact to form C3 convertase, which is identical in function to the C3 convertase formed by the alternative pathway, and it works to cleave C3 into C3a and C3b more quickly. Finally for this pathway, a molecule of C3b interacts with the preexisting C3 convertase complex, forming the C5 convertase complex that cleaves factor C5 into C5a and C5b.The final pathway that leads to this point is the classical complement pathway. This pathway is activated by the binding of aggregated antibody-antigen complexes, as well as components of viral and bacterial cells such as lipopolysaccharides, to the C1q protein. C1q is part of the C1 complex, which also includes C1s and C1r. Binding of a substance to C1q causes a conformational change in C1r and C1s, allowing C1s to become an active protease, which then is able to cleave complement factors C2 and C4 into their a and b fragments, as in the lectin pathway. The remainder of the pathway is identical to that of the lectin pathway. Finally, after cleavage of C5 into C5a and C5b by any of the pathways, complement componenets C6, 7, 8 and 9 can interact with component C5b in order to form the membrane attack complex. This complex attaches to the plasma membrane of pathogen cells, forming a hole in the membrane and allowing diffusion of molecules in the cell, and eventually cell death if enough attack complex form.


Alternative Complement Pathway,Protein

The alternative complement pathway is a component of the immune system's natural defence against infections. It is a pathway that opsonizes and kills pathogens. The pathway is triggered when the C3b protein directly binds to a microbe, or by an interaction with foreign materials and damaged tissues. The pathway triggers the binding of plasma protein factor B, which allows factor D to cleave factor B into Ba and Bb. Bb remains bound to C3(H2O) to form C3(H2O)Bb (also known as a fluid-phase C3-convertase). This convertase then cleaves multiple C3 proteins into C3a and C3b. The complex is believed to be unstable until it binds properdin, a serum protein. The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b to form alternative pathway C5-convertase.The C5-convertase of the alternative pathway consists of (C3b)2BbP (sometimes referred to as C3b2Bb). C5-convertase then cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, C8 and then to multiple molecules of C9 to form membrane attack complex.


Ubiquitin–Proteasome Pathway,Protein

The ubiquitin-proteasome pathway is the pathway in which molecules, specifically proteins, are broken down into smaller molecules in the cytosol or in the nucleus.This pathway subsequently has effects in many other pathways and processes. This pathway uses 2 distinct steps. The first step is that the protein being broken down is tagged by multiple ubiquitin units attaching to the protein. The second step is that the protein that has been  tagged degrades as it is catalyzed by the 26S proteasome. This pathway is important for DNA repair, regulating the amount of proteins, and the creation of antigen-peptide.


Lectin-Induced Complement Pathway ,Protein

The lectin-induced complement pathway, also known as the MBL pathway, is a complement activation pathway that is triggered by mannose-binding lectin binding to sugars found on carbohydrates found on pathogens. Unlike other complement pathways, this pathways components do not bind directly to the antibodies attached to the pathogen. The bacteria that MBL binds to include listeria, salmonella, and HIV-1.


Toll-Like Receptor Pathway 1,Protein

Toll-like receptors (TLRs) are part of the innate immune system. These receptors recognize pathogen-associated molecular patterns from different microbes. TLR2 recognizes a variety of PAMPs including lipoproteins, peptidoglycans, lipotechoic acids, and mannan. TLR3 recognizes viral double-stranded RNA, small interfering RNAsa, and self-RNAs. TLR4 recognizes lipopolysaccharides. TLR7 recognizes single-stranded RNA. TLR9 recognizes bacterial and viral DNA with unmethylated CpG-DNA motifs. TLRs are synthesized in the endoplasmic reticulum, moved to the Golgi, and then recruited to the cell surface or intracellular compartments. TLRs recruit adaptor molecules such as MYD88, TRIF, TIRAP, or TRAM leading to the activation of transcription factors NF-kappa-B causing innate immune responses. MYD88 is recruited by all TLRs. Adaptor TIRAP recruits MYD88 to cell surface TLRs, including TLR2 and TLR4. TLR signaling molecule IRAK1 activation activates TRAF6 causing the activation of IKK complex then NF-kappa-B and kinases. Activated TRAF6 promotes polyubiquination of TRAF6 and TAK1, TAB1, TAB2 complex. TAK1 activates pathways causing activation of IKK complex and NF-kappa-B and MAPK pathways. The IKK complex phosphorylates and activates IKK-beta. IKK complex also phosphorylates I-kappa-B-alpha allowing dissociation and translocation of NF-kappa-B to the nucleus resulting in proinflammatory gene expression. Activated TAK1 complex also activates p38 and JNK, regulating the activation of AP-1 transcription factors to regulate inflammatory responses. Many transmembrane molecules, such as glycophosphatidylinositol-anchored protein CD14, also regulate TLR signaling pathways.


Classical Complement Pathway,Protein

The classical complement pathway is a pathway that is responsible for activating the complement system within the immune system. This pathway begins with the activation of antibodies IgM and IgG. Protein C3 is created, and after a series of reactions, cleaves the C5 protein. This brings phagocytes to the infected area and sets the stage for the coming together of the membrane attack complex (MAC). This complex targets the cell and creates an opening in the membrane, which leads to cell lysis and death.


CXCR4 Signaling Pathway,Protein

CXCR4 is a chemokine G-protein-coupled receptor. Chemokine receptors couple to the pertussis toxin-sensitive Gi proteins. It is involved in organogenesis, hematopoiesis, and the immune response. Chemokine stromal cell-derived factor 1 (SDF-1) binds CXCR4. CXCR4 is also a co-receptor for HIV and is involved in the metastasis of some cancers. Pertussis toxin ADP-ribosylates guanine nucleotide binding protein alpha inhibiting (Gai) proteins inhibiting GPCR/Gi coupling. Activated Gai inhibits adenylyl cyclase and activates tyrosine kinases, while activated guanine nucleotide binding protein beta and gamma activate PI3K - regulating gene transcription, cell migration, and cell adhesion. PLC is activated to cause the cleavage of PIP2 to IP3 and DG. This leads to the increase of calcium from the endoplasmic reticulum and the activation of protein kinase C.


D4-GDI Signaling Pathway,Protein

Perforin protein forms pores in the membrane to allow for granzyme B to enter the cell.  Granzymes induce apoptosis by activating caspases.  D4-GDP dissociation inhibitor (D4-GDI) is a negative regulator of ras-related Rho Family of GTPases.  D4-GDI binds Rho GTPases to keep the Rho protein in a GDP-bound and inactivate state.  Caspase 3 cleaves D4-GDI into two fragments of 5 kDa and 23 kDa size.  The 23 kDa fragment translocates to the nucleus to activate Jun kinase, a regulator of apoptosis.  Poly (ADP-ribose) polymerase-1 (PARP) is a substrate for caspase-3.  Caspase-3 cleaves PARP into various fragments, this is a hallmark of apoptosis.  PARP functions to detect and repair DNA damage.  Cleavage of PARP by caspase prevents DNA repair, contributing to cell death.  RHO GTPases become activated when released from D4-GDI upon cleavage by caspase-3.  RHO GTPases mediate cytoskeleton changes leading to apoptosis and cell death.  .


T Cell Receptor Signaling Pathway ,Protein

The T-cell receptor signalling pathway is an intracellular pathway that depicts how T-cells are activated as part of the cell-mediated immune response. T-cells are a type of lymphocyte produced by the thymus gland (T stands for thymus) that have a unique protein on their surface called the T-cell receptor. The T-cell receptor (TCR) is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules (PMID: 6336315). T-cells are activated when they encounter another immune cell such as a dendritic cell or a B-cell that has digested a protein antigen and displayed the resulting peptide antigen fragments on their surface MHC molecules. These antigen-bound dendritic or B-cells are called antigen-presenting cells or APCs. The MHC-antigen complex from these APCs binds to the TCR of a given T-cell and then, through a series of signalling events (depicted in this pathway), the T-cell begins to secrete cytokines (PMID: 19132916).  Some cytokines help the T-cell mature while other cytokines spur the growth of even more T-cells. The MHC-antigen-TCR binding event activates several signalling pathways such as the PI3K pathway that generates inositol triphosphate (IP3) at the plasma membrane. This leads to the recruitment of signalling molecules like PDK1 (pyruvate dehydrogenase kinase 1), PLC-gamma-1 (phospholipase C-gamma), diacylglycerol (DAG) and others that are essential for the activation of PKC-theta (protein kinase C-theta), and eventually the production of interleukin-2 (IL-2) as well as other cytokines (PMID: 19132916). As shown in this pathway the antigen is first presented to the T-cell receptor (consisting of an alpha and beta subunit) and the CD3 glycoprotein complex (PMID: 19132916). An early event in TCR activation is the phosphorylation of certain tyrosine containing motifs on the cytosolic side of the TCR/CD3 complex by a protein known as lymphocyte protein tyrosine kinase or Lck. After this phosphorylation event, a protein called the zeta-chain associated protein kinase (Zap-70) is recruited to the phosphorylated TCR/CD3 complex where it becomes activated (PMID: 7539035). This promotes the recruitment and phosphorylation of other proteins. For instance, the phosphorylation of SLP-76 by Zap-70 promotes the recruitment of a protein known as Vav (a guanine nucleotide exchange factor), as well as the adaptor proteins NCK and GADS, and an inducible T cell kinase known as Itk. Phosphorylation of PLC-gamma-1 by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the secondary messengers known as diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates PKC-theta and the MAPK/Erk pathways, both promoting transcription factor NF-kappa-B activation. IP3 triggers the release of calcium from the endoplasmic reticulum, which promotes entry of extracellular Ca2+ into the T-cells where it is bound by calmodulin. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase known as calcineurin (PMID: 22100452), which promotes IL-2 gene transcription through the transcription factor NFAT (Nuclear factor of activated T-cells) (PMID: 3260404).


Stat3 Signaling Pathway,Protein

The STAT3 signalling pathway is a pathway activated by many different cytokines. It has also been found to be activated by many carcinogens. Cytokines are small proteins. These proteins are released by some of the cells in the immune system, and are vital to signalling pathways in the body of mammals. STAT3 is very important in the activation of the expression of certain mediators in the liver.  STAT3 binds at the phosphotyrosine receptor which in turn phosphorylates tyrosine 705 at the C-terminal domain of STAT3, activating STAT3. If a receptor is missing tyrosine-kinase activity it will find tyrosine-kinases that are associated to the receptor, including JAK and Src when it is time for ligand engagement. Thanks to this recruitment,  STAT3 is phosphorylated through the tyrosine phosphorylation cascade. This means that STAT3 is now activated, and its compounds disconnect from the receptor site, and relocate to the nucleus. Once there, the compounds bind to DNA response elements, and take part in many processes against target genes, such as apoptosis and cell proliferation, regulating their transcription.


Toll-Like Receptor Pathway 2,Protein

Toll-like receptors (TLRs) are a type of pattern recognition receptor that spans the cell membrane and recognizes conserved microbial molecules. TLRs get their name from the toll gene in Drosophila, which produces a protein that is similar in structure to TLR proteins. Each TLR is able to recognize specific unique molecules associated with pathogens, including lipoproteins, lipopolysaccharides, double stranded RNA, flagellin and others. Recognition of pathogen molecules allows the immune system to detect extracellular pathogens.TLR2 can form heterodimers on the surface of the cell's plasma membrane with either TLR1 or TLR6. These dimers, along with another protein known as CD14 as a cofactor, can detect different microbial lipoproteins. Following binding of lipoproteins to these complexes, they activate a protein known as myeloid differentiation primary response protein (MyD88). MyD88 then joins with interleukin-1 receptor-associated kinase 1 (IRAK1) to form a complex.TLR4 is another TLR that detects lipopolysaccharides (LPS) that make up the outer membrane of Gram-negative bacteria. It associates with two other proteins, monocyte differentiation antigen CD14, and lymphocyte antigen 96 (MD2), which allow it to better bind LPS. Once LPS has bound to the complex, it activates signalling to the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) and Toll-interacting protein (TOLLIP), which then recruit MyD99 and IRAK1 to the TLR on the cell surface.Other TLRs have slightly more simple pathways, including TLR9, which recognizes CpG-DNA, which is a section of DNA with a cytosine followed by a guanine and are found commonly in pathogen genomes. TLRs 3 and 8 both recognize double stranded RNA, which is found in some viruses. TLR7 recognizes single stranded RNA from internalized viral genomes, and can also be activated by the drug Imiquimod, sold as Aldara. Imiquimod is used to treat genital warts , actinic keratosis and basal cell carcinoma by activating the immune system in the area it was applied. Finally, TLR5 recognizes the bacterial flagellin proteins. When any of these substances bind their respective TLRs, the TLRs signal to the MyD88 and IRAK1 complex.After any of these activation mechanisms occurs, the IRAK protein, which is a kinase, phosphorylates  and activates TNF receptor-associated factor 6 (TRAF6). TRAF6 then interacts with the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT). ECSIT then activates mitogen-activated protein kinase kinase kinase 1 (MAP3K1). This then phosphorylates the IKK complex, comprised of inhibitors of nuclear factor kappa-B kinase subunits alpha and beta (IKKA and IKKB), as well as its regulatory subunit, NF-kappa-B essential modulator (NEMO). Another pathway starting with the activation of TRAF6 leads to this same point. First, TRAF6 activates a complex consisting of mitogen-activated protein kinase kinase kinase 7 (MAP3K7), as well as TGF-beta-activated kinase 1 (TAK1) and MAP3K7-binding proteins 1, 2 and 3. This complex can then activate dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4), which then phosphorylates mitogen-activated protein kinase 8 (MAPK8) in the cell nucleus. Alternately, the TAK1 and MAP3K7-binding complex can phosphorylate and activate mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates the IKK complex. NF-kappa-B is a transcription factor that is inhibited by NF-kappa-B inhibitor alpha, which binds to it and blocks its nuclear localization sequence, holding it in the cytoplasm rather than allowing it to enter the nucleus and transcribe the DNA. However, the IKK complex is able to phosphorylate the inhibitor, removing it and allowing nuclear factor NF-kappa-B p105 subunit and transcription factor p65 to enter the nucleus to transcribe DNA and allow the appropriate immune response for the stimulus to be activated.


EPO Signaling Pathway,Protein

The hormone erythropoietin, is a 166 amino acid protein with an apparent molecular weight in  its native form of 39,000 Da. The molecule is heavily glycosylated since its mass derived from its amino acid content is 18,398. The selective interaction of a hormone with its target cells is usually mediated by cell membrane receptors specific for the particular hormone. Erythropoietin-responsive cells have a trypsin-sensitive receptor for the hormone which requires protein synthesis for its maintenance. Erythropoietin-responsive cells can interact with other hematopoietic growth factors, and such interactions may lead to competition for pathway-specific differentiation, particularly under conditions of high cell density. The amino-terminal region of the hormone is not involved in receptor binding.


FAS signaling pathway ( CD95 ),Protein

Fas ligand is a transmembrane protein part of the tumor necrosis factor (TNF) family. It plays a role in inducing apoptosis and is an important regulator of the immune system. Fas ligand signals through the Fas receptor on target cells. Fas ligand binds to the receptor and forms the death-inducing signalling complex, including the Fas-associated death domain, death-domain associated protein, and caspase-10. Caspases are synthesized as inactive pro-caspases. Caspases are are proteases that cleave their substrates. Caspase-8 is an initiator caspase that is activated in response to pro-apoptotic stimulus and causes a cascade of further caspase activity by cleaving and activating effector caspases, like caspases -3 and -7.  Once activated, caspases -3 and -7 cleave downstream proteins. Caspase-8 activity is regulated by CASP8 and FADD-like apoptosis regulator. Kinases activate mitogen-activated protein kinases which activate pro-apoptotic JNK activity.


BCR Signaling Pathway,Protein

The BCR signalling pathway is a pathway that plays a vital role in the development and all other functions of B-cells, which means it is vital for the immune response. The BCR, also known as the B-cell receptor, is usually found on the outer membrane of B-cells. B-cells grab antigens from immune synapses, through a number of processes including cell spreading and receptor transport. After these have been performed, endocytosis and antigen-presentation occur. B-cells manipulate the dynamic of BCR-antigen bonds. They group and spread the antigen, increasing the relation with BCR, which creates sensitivity. The two main functions of the BCR pathway is to signal transduction, and the second is to prepare the antigen for processing by the helper T cells. Any defects in this pathway may lead to the patient being immunodeficient, or having B-cell malignancy.


Cardiolipin Biosynthesis (Barth Syndrome),Disease

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism. (Wikipedia) Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor. Newly synthesized cardiolipins undergo remodeling, a process carried out by the enzyme tafazzin. A mutated tafazzin gene disrupts this post-synthetic remodeling and causes Barth syndrome (BTHS), an X-linked human disease (PMID: 16973164). BTHS patients seem to lack acyl specificity and consequently, many potential cardiolipin species can exist (PMID: 16226238).


Succinate Signalling,Protein

Tricarboxylic acid (TCA) cycle intermediates can function as inflammatory signals. Succinate enhances glycolysis in several ways. It inhibits prolyl hydroxylase domain (PHD) enzyme function, both directly by product inhibition and indirectly via reactive oxygen species (ROS), driving hypoxia-inducible factor-1α (HIF-1α) accumulation and increased glycolysis. ROS also inhibit mitochondrial function, boosting glycolysis as a result. Elevated HIF-1α enhances the expression of genes containing HIF response elements (HREs), including the interleukin 1β (IL-1β) gene. Succinate can signal through succinate receptor 1 (SUCNR1) and act in synergy with Toll-like receptors (TLRs) to boost dendritic cell function. NAD+ exerts several anti-inflammatory effects by activating sirtuins, a class of NAD+-dependent deacetylases. Finally, inactivation of Sirt3 has been demonstrated to enhance NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation.


NAD+ Signalling Pathway (Cancer),Signaling

NAD+-dependent signalling pathways regulate many fundamental processes such as DNA repair, DNA transcription, cell proliferation, cell survival, cell cycle progression, apoptosis, and metabolism. These pathways are all linked to cancer development. Degradation of NAD will activate various biosynthetic pathways, which are crucial for incessant cancer cell proliferation.


NAD+ Signalling and Aging,Signaling

An interesting link has emerged between NAD+ metabolism, SIRT1, SIRT3, and mitochondrial function. NR and PARP inhibitors increased life span in worms via activation of the mitochondrial unfolded protein response UPRmt by sir2.1. Short-term (1 week) supplementation of these mice with NMN restored mitochondrial homeostasis in muscles, which suggests that NAD+ supplementation can restore some reversible aspects of the aging process. Both observations are consistent with the model indicating that an imbalance in the relative stoichiometries of mitochondria- versus nucleus-encoded ETC proteins may induce life-span extension via activation of the UPRmt. In support of such a mechanism, mutation or reduced function in nuclear genes encoding ETC components in yeast, Caenorhabditis elegans, Drosophila, and mice increase life span through activation of the mitochondrial unfolded protein response UPRmt. NAD salvage pathway is deficient in aging since the supplementation with NMN corrects defects associated with aging.


Succinate Signalling During Inflammation,Protein

Succinate induces calcium mobilization in an adenylyl cyclase (AC) and protein kinase A (PKA)-dependent manner. Succinate receptor 1 (SUCNR1) engagement activates phospholipase C (PLC), resulting in the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers induce calcium mobilization and PKC activation, respectively, and subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) production as well as p38 activation. PKC-dependent phosphorylation of extracellular signal-related kinases ERK1/2 can also drive PG production. SUCNR1 signaling might act in synergy with several inflammatory signaling cascades. PKA is known to phosphorylate and activate the p65 subunit of nuclear factor κB (NF-κB) and cAMP response element-binding protein (CREB). Furthermore, NF-κB, activating protein (AP)-1, nuclear factor of activated T cells (NFAT), and ETS domain-containing protein (Elk-1) are all downstream targets of PKC and MAPKs.


Bile Acid Direct Signalling Pathway (1),Signaling

Bile acids are synthesized in the liver and stored in the gallbladder. After eating, bile acids are released from the gallbladder into the small intestine. The majority of bile acids are transported back to the liver, but some may then escape enterohepatic circulation to enter systemic circulation. The bile acids, deoxycholic acid (DCA) and chenodeoxy cholic acid (CDCA), may interact with gap junction proteins to cross the blood-brain barrier. Bile acids are endogenous ligands for farnesoid X receptor (FXR) and G-protein coupled BA receptor 1 (TGR5) and once they have crossed the blood brain barrier, the bile acids may interact with these receptors. FXR is a regulator of secretion and transport of bile acids. TGR5 receptor activation increases cAMP synthesis and activates the mitogen-activated protein kinase (MAPK) pathway. TGR5 regulates the use of energy and is a target of interest for metabolic disorders.


Bile Acid Indirect Signalling Pathway,Signaling

Bile acids are taken up by enterocytes, epithelial cells of the small intestine, where they can activate the nuclear receptor farnesoid X receptor (FXR). This causes the production of fibroblast growth factor 19 (FGF19) which is then transported out of the enterocyte to the portal vein. While most FGF19 goes to the liver, some FGF19 instead enters systemic circulation where it can cross the blood brain barrier and interact with its receptors in the brain. Beta-klotho is a transmembrane protein that promotes the interaction of FGF19 and the receptor to form a stable complex. FGF receptor signaling likely plays a role in energy and glucose metabolism.


Bile Acid Direct Signalling Pathway (2) ,Signaling

In the intestine, L-cells (enteroendocrine cells) can produce glucagon-like peptide 1 (GLP-1) after bile acid activates G-protein coupled bile acid receptor 1 on L-cells. Only small portion of GLP-1 can enter the systemic cirulation, and most of GLP-1 are degraded by dipeptidyl peptidase-4. Therefore, only small portion of GLP-1 can eventually across blood-brain barrier to interact with GLP-1 receptors


CD40L Signalling Pathway,Protein

CD40 is a part of the tumor necrosis factor (TNF) receptor superfamily. When bound to it’s main ligand CD40L, also known as CD154, CD40-CD40L interaction initializes the activation and proliferation of B lymphocytes or results in carcinoma cells apoptosis.CD40 can be expressed on many different cell surfaces such as endothelial cells, fibroblasts, hematopoietic progenitors, platelets, and basal epithelial cells. When combined with the variety of environments CD40 presenting cells can be in, the differing effects resulting from CD40 signalling is vast. However, one characteristic all CD40 mediated signalling has in common is that instead of using kinase to mediate signal transduction, signalling is performed through downstream adapter molecules. Some pathways activated by CD40-CD40L signalling include the activation of nuclear factor-κB, p38 mitogen activated protein kinase, c-Jun-NH2-kinase, signal transducers and activators of transcription, and phosphoinositide 3-kinase pathways. All of which ultimately help regulate alterations in gene expression.


G-Protein Signaling Through Tubby Proteins,Protein

Tubby protein is a part of a family of proteins called Tubby Like Proteins (TULP) characterized by 260 amino acids that form a helix-filled barrel structure at the carboxylic acid terminal (Tubby domain). Using its Tubby domain to bind phosphatidylinositol 4,5-bisphosphate (PIP2), Tubby proteins are able to localize on the plasma membrane. Through the receptor mediated activation of G-proteins, the enzyme phospholipase C–beta (PLC-beta) hydrolyses PIP2 releasing tubby from the plasma membrane. This triggers protein translocation of tubby to the nucleus allowing tubby to act as a transcription regulator.


g-Secretase Mediated ErbB4 Signalling Pathway,Protein

The HER4/erbB4-encoded protein, is a transmembrane receptor that contains a cytoplasmic tyrosine kinase domain. This domain exhibits almost 80 percent homologness with the corresponding domain of EGFR (the epidermal growth factor receptor). It was discovered in the 1990s by Plowman et al, that heregulin was responsible for inducing tyrosine phosphorylation of HER4/erbB4. ErbB4 (HER4) receptor is classified as type I GFRs. Where the tyrosine kinase growth factor receptors (GFRs) have been sub-classified into 9 different families based on the structure of their extracellular ligand binding and intracellular kinase domains and the manner in which such protein induce the ligands. Experiments revealed that erbB4 has is readily findable in heart, spleen, breast, muscle, pituitary, kidney, parathyroid, brain, and testis.


Ion Channel and Phorbal Esters Signaling Pathway,Protein

Molecules transmitting signals into cells often act through receptors in the plasma membrane that stimulate production of second messengers. When activated by a plasma membrane receptor, the enzyme phospholipase C (PLCg) hydrolyzes the membrane lipid phosphatidylinositol (PIP2) into the second messengers diacylglycerol (DAG) and IP3. IP3 releases calcium from intracellular stores into the cytoplasm where calcium alters many cellular activities, including activating protein kinase C. DAG also activates protein kinase C. Biologists often study signaling by artificially manipulating pathways using molecules like ionomycin and phorbol esters as research tools. Ionomycin is a molecule that carries calcium through the plasma membrane to increase the calcium concentration in the cytoplasm and activate protein kinase C without activating phospholipase C. Phorbol esters are molecules that mimic the action of DAG in the activation of protein kinase C, and were originally identified as tumor-promoting agents. The combination of ionomycin and phorbol esters is often used experimentally to study the effect of calcium and DAG signaling in cellular responses like T cell activation.


Circadian Rhythms,Protein

The nuclear entry of clock gene products is required to establish the negative feed back loop- a key step in proper circadian rhythm. Heterodimerization of clock proteins PER and CRY is required for translocation to the nucleus. Nuclear entry of PER can be regulated by mammalian casein kinase I (CK1). Once in the nucleus, PER and CRY proteins appear to differentially inhibit the transactivation by CLOCK/BMAL1. Proteins like REV-ERBa and DEC also regulate the transcriptional activation by CLOCK/BMAL1. In addition, CRY, PER, and BMAL1-CLOCK play bidirectional roles in transcription resulting in interactivating feedback loops. The expression of BMAL1 and CLOCK can be upregulated by CRY and PER. Such loops are believed to be important in the stability and persistence of circadian rhythm.


Hop Pathway in Cardiac Development,Physiological

Homeodomain transcription factors comprise a large family of DNA binding factors that regulate transcription and development. Many homeodomain genes arranged in genomic clusters determine anterior-posterior patterning, while others determine the fate of cells in specific tissues. The proliferation of cardiac myocytes and their differentiation early in development are both dependent on the coordinate expression and action of serum response factor (SRF), GATA4 and the homeodomain factor Nkx2-5. All three of these factors are expressed in developing cardiomyocytes and induce expression of cardiac genes. Disruption of the Nkx2-5 gene in mice leads to embryonic lethality and defective cardiac development. SRF also plays a duel role in cardiac development, influencing both cardiomyocyte proliferation and differentiation depending on the stage and other signals that are present.In addition, the Hop (Homeodomain Only Protein) gene encodes a factor expressed early in cardiac development that is involved in cardiac differentiation. Hop inactivation in vertebrates leads to severe defects in cardiac development, acting downstream of Nkx2-5. Cardiac cells from mice lacking the Hop gene fail to exit the cell cycle in the normal manner, continuing to proliferate past the normal developmental stage. Many of the genes disregulated in the absence of Hop are involved in the cell cycle and are also targets of SRF. Although Hop is a homeodomain protein, it lacks a DNA-binding domain indicating that it must not regulate gene expression directly. Hop appears to regulate the expression of cardiac genes by binding to SRF and blocking DNA binding of SRF. The sequestration of SRF by Hop blocks the activation of cardiac genes, preventing normal cardiac development. The influence of Hop on the opposing processes of cardiomyocyte differentation and proliferation reflect the interaction of Hop with SRF and the duel role SRF plays. In early cardiac development, Hop opposes differentiation induction by SRF, while at later stages Hop opposes the proliferation induced by SRF.


LPS and Citrate Signaling and Inflammation,Protein

Citrate is an important substrate in cellular energy metabolism, which is produced by mitochondria and used in Krebs cycle or released into cytoplasm through a specific mitochondrial carrier, CIC. In the cytosol, citrate and its derivatives, acetyl-CoA and oxaloacetate, are used in normal and pathological processes. Apart from the classical role as metabolic regulator, citrate is also involved in inflammation, cancer, insulin secretion, histone acetylation, neurological disorders and non-alcoholic fatty lever disease.


Protein Synthesis: Alanine,Protein

Protein synthesis is an essential life process that builds the important large amino acid macromolecules that function as enzymes, antibodies, and cellular structural components. Although synthesis begins with the transcription of DNA into RNA, this pathway depicts the reactions that occur during translation. Transcribed messenger RNA (mRNA), which contains the genetic code to direct protein synthesis, is transported out of the nucleus and becomes bound to ribosomes in the cytoplasm or endoplasmic reticulum. The amino acids required to assemble polypeptide chains are delivered to the ribosomes using transfer RNA (tRNA). Each tRNA molecule has both a binding site for a specific amino acid and a three-nucleotide sequence called the anticodon that forms three complementary base pairs with an mRNA codon. Charging or loading the appropriate amino acid onto its tRNA is carried out by an aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase. This enzyme catalyzes the esterification of an amino acid to one of all its compatible tRNAs to form an aminoacyl-tRNA. Each of the twenty amino acids has a corresponding aa-tRNA made by a specific aminoacyl-tRNA synthetase. Ribosomes match the anticodons of the charged tRNA molecules with successive codons of the mRNA. After a match is found, the ribosome transfers the amino acid from the matching tRNA onto the growing peptide chain via a reaction termed peptide condensation, and the tRNAs, no longer carrying amino acids, are released.


Protein Synthesis: Aspartic Acid,Protein


Protein Synthesis: Glutamic Acid,Protein


Kidney Function- Proximal Convoluted Tubule,Physiological

The proximal convoluted tubule is part of the nephron between the Bowman's capsule and the loop of Henle. The proximal convoluted tubule functions to reabsorb sodium, water, and other ions. Sodium and bicarbonate (hydrogen carbonate) are transported by a co-transporter that is responsible for the majority of sodium reabsorption. The bicarbonate, along with hydrogen, are exchanged across the basal and apical membranes, respectively, to effectively regulate the pH of the filtrate.  In addition, chloride ions are not normally reabsorbed in large amounts at the proximal tubule compared to other parts of the nephron.  However, the reabsorption of chloride, as well as potassium, increases as the amount of water reabsorption increases due to solvent drag (also known as bulk transport).  This occurrence explains solute movement secondary to water flow.  All the cation and anion transport creates a gradient favourable for ion and water reabsorption, leading to an increase in blood pressure.


Kidney Function - Descending Limb of the Loop of Henle,Physiological

The loop of Henle of the nephron can be separated into an ascending limb and the descending limb.  The ascending limb is highly impermeable to water, but permeable to solutes.  Conversely, the descending limb is highly impermeable to solutes such as sodium, but permeable to water.  As solutes are being actively transported out of the ascending limb, the solutes cause in increase in osmotic pressure.  This, combined with the ability for water to move freely out of the descending limb, leads to a water reabsorption into the adjacent capillary network and a high concentration of sodium in the filtrate at the descending Limb.  Water moves from the descending loop to the capillary network through aquaporin channels in the cell membrane.


Kidney Function - Ascending Limb of The Loop of Henle,Physiological

The loop of Henle of the nephron can be separated into an ascending limb and the descending limb.  The descending limb is highly impermeable to solutes such as sodium, but permeable to water.  Conversely, the ascending limb is highly impermeable to water, but permeable to solutes. Chloride, potassium, and sodium are co-transported across the apical membrane (closest to the lumen) via transporters from the filtrate. The transporter requires all three ions present to be effective and to maintain electroneutrality. In addition, the three ions are transported across the basolateral membrane (closest to the renal interstitium) via other means such as the sodium potassium ATPase transports and the chloride channels in the membrane. As these solutes are being actively transported out of the ascending limb and into the renal interstitium/capillary network without water following (due to the lack of water permeability), the filtrate becomes more diluted. Furthermore, these ions simultaneously causes an increase in osmotic pressure that contributes to water reabsorption in the descending limb.  This effect can be magnified with the help of vasopressin, which is a hormone that is typically involved with water reabsorption.  However, when it acts on the ascending limb, it aids in increasing sodium reabsorption which will increase water reabsorption in the latter parts of the nephron (the distal tubule and collecting duct).


Kidney Function - Collecting Duct,Physiological

The collecting duct of the nephron is the last segment of the functioning nephron and is connected to minor calyces and the ensuing renal pelvis of the kidney where urine continues before it is stored in the bladder.  The collecting duct is mainly responsible for the excretion and reabsorption of water and ions. It is composed of two important cell types: intercalated cells that are responsible for maintaining acid-base homeostasis, and principal cells that help maintain the body's water and salt balance.  When renin is released from the kidneys, it causes the activation of angiotensin I in the blood circulation which is cleaved to become angiotensin II. Angiotensin II stimulates the release of aldosterone from the adrenal cortex and release of vasopressin from the posterior pituitary gland.  When in the circulation, vasopressin eventually binds to receptors on epithelial cells in the collecting ducts.  This causes vesicles that contain aquaporins to fuse with the plasma membrane.  Aquaporins are proteins that act as water channels once they have bound to the plasma membrane.  As a result, the permeability of the collecting duct changes to allow for water reabsorption back into the blood circulation.  In addition, sodium and potassium are also reabsorbed back into the systemic circulation at the collecting duct via potassium and sodium channels. However, aldosterone is a major regulator of the reabsorption of these ions as well, as it changes the permeability of the collective duct to these ions.  As a result, a high concentration of sodium and potassium in the blood vessels occurs. Some urea and other ions may be reabsorbed as well. The reabsorption of ions and water increases blood fluid volume and blood pressure.


Kidney Function - Distal Convoluted Tubule,Physiological

The distal convoluted tubule of the nephron is the part of the kidney between the loop of henle and the collecting duct. When renin is released from the kidneys, it causes the activation of angiotensin I in the blood circulation which is cleaved to become angiotensin II. Angiotensin II stimulates the release of aldosterone from the adrenal cortex and release of vasopressin from the posterior pituitary gland.  When in the circulation, vasopressin eventually binds to receptors on epithelial cells in the distal convoluted tubule.  This causes vesicles that contain aquaporins to fuse with the plasma membrane.  Aquaporins are proteins that act as water channels once they have bound to the plasma membrane.  As a result, the permeability of the distal convoluted tubule changes to allow for water reabsorption back into the blood circulation. In addition, sodium, chlorine, and calcium are also reabsorbed back into the systemic circulation via their respective channels and exchangers. However, aldosterone is a major regulator of the reabsorption of these ions as well, as it changes the permeability of the distal convoluted tubule to these ions.  As a result, a high concentration of sodium, chlorine, and calcium in the blood vessels occurs. The reabsorption of ions and water increases blood fluid volume and blood pressure.


Pancreas Function - Beta cell,Physiological

Beta cells are found in pancreatic islet cells and their main function is to release insulin.  Insulin counteracts glucagon and functions to maintain glucose homeostasis when glucose levels are high.  Insulin is contained in granules in the cell as a reserve ready to be released, which is dependent on extracellular glucose levels, and intracellular calcium levels and/or various proteins that activate the vesicle-associated membrane protein on the insulin granules' membranes.  In the process of insulin secretion, glucose must first undergo glycolysis to increase ATP in the cell.  The inside of the beta cell then becomes electrically positive due to the closure of potassium channels that were inhibited by ATP.  From this closure, the potassium is no longer being shuttled out of the cell, thus depolarizing the cell due to the extra intracellular potassium.  The resulting action potential from the increased membrane potential causes the voltage gate calcium channels to open, creating an influx of calcium into the cell.  This triggers the vesicle-associated membrane protein on the outside of the insulin granule to tether, dock, and fuse with the beta cell membrane.  Insulin is then exocytosed from the cell.  However, the vesicle-associated membrane protein can be activated by other means in addition to calcium.  Acetylcholine can bind to muscarinic acetylcholine receptors on the cell membrane and trigger a G protein cascade.  This eventually leads to the activation of inositol trisphosphate to cause calcium release from the rough endoplasmic reticulum so that it can activate the calcium/calmodulin-dependent protein kinase to trigger the vesicle-associated membrane protein.  The G protein cascade can also lead to the activation of diacylglycerol and subsequently protein kinase C to lead to the same outcome.  Glucagon-like peptide can also trigger a similar G protein cascade when it binds to glucagon-like peptide receptors on the cell membrane of the beta cell.  This process involves cAMP and a few other proteins in order to lead to the same eventual outcome of triggering the vesicle-associated membrane protein and the exocytosis of insulin from the beta cell.


Pancreas Function - Alpha cell,Physiological

Alpha cells are a type of islet cell found in the pancreas that release glucagon. Glucagon counteracts insulin and functions to maintain glucose homeostasis when detected glucose levels are low. Glucagon is contained in granules in the cell as a reserve ready to be released. Extracellular glucose levels and ion channels regulate the secretion of glucagon.  Glucose undergoes glycolysis to increase ATP in the cell. The moderate activity of potassium ATP channels causes the membrane potential to be around -70mV. The alpha cell then becomes electrically active due to the closure of potassium channels. The cell membrane becomes depolarized due to voltage dependent sodium, potassium and calcium channels. This causes an increase in action potentials and opens voltage gate calcium channels causing an increase of calcium into the cell. This triggers the exocytosis of glucagon from the cell.  Conversely, an increase in extracellular glucose leads to an increase in ATP production and inhibition of potassium ATP channels. The membrane depolarizes to a membrane potential that inactivates voltage dependent calcium channels. This results in decreased intracellular calcium and inhibits exocytosis of glucagon.


Mevalonate Pathway,Metabolic

The Mevalonate Pathway is a necessary pathway that occurs in archaea, eukaryotes and select bacteria. It has mainly been studied with regard to cholesterol biosynthesis and how it relates to cardiovascular disease in humans, but has recently garnered attention for its many other essential roles within human pathology.  The pathway begins in the cytoplasm with acetyl-CoA and acetoacetyl-CoA, which interact with acetyl-CoA acetyltransferase, coenzyme A and water to synthesize hydroxymethylglutaryl-CoA synthase. In turn, this synthase teams up with coenzyme A and a hydrogen ion in the endoplasmic reticulum to create 3-hydroxy-3-methylglutaryl-CoA. 3-Hydroxy-3-methylglutaryl-CoA then pairs with 2NADPH, 2 hydrogen ions and is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase to produce (R)-mevalonate, also producing byproducts CoA and NADP. Exiting the endoplasmic reticulum, and entering the peroxisome, (R)-mevalonate uses the help of ATP and mevalonate kinase to create mevalonic acid (5P). This piece is especially important to the human species as decreased activity of the enzyme mevalonate kinase has been found to be a direct link to two auto-inflammatory disorders: MVA and HIDS. Using phosphomevalonate kinase and ATP, the pathway re-enters the cytoplasm and mevalonic acid (5P) converts to (R)-mevalonic acid-5-pyrophosphate and ADP. (R)-mevalonic acid-5-pyrophosphate, ATP and diphosphomevalonate decarboxylase work together to create phosphate, carbon dioxide, ADP and isopentenyl pyrophosphate. Re-entering the peroxisome, isopentenyl diphosphate delta isomerase 1 is waiting to propel isopentenyl pyrophosphate into dimethylallylpyrophosphate. This pushes the pathway back into the cytoplasm, where another isopentenyl pyrophosphate molecule and the enzyme farnesyl pyrophosphate synthase create pyrophosphate and geranyl-PP. Yet another isopentenyl pyrophosphate molecules works with farnesyl pyrophosphate synthase to produce pyrophosphate and farnesyl pyrophosphate. Now in the endoplasmic reticulum membrane, 2 farnesyl pyrophosphate molecules with the help of NADPH and a hydrogen ion catalyze with squalene synthase and create squalene. This is an important first step in the specific hepatic cholesterol pathway. Remaining in the endoplasmic reticulum membrane, squalene, FMNH, oxygen and squalene monooxygenase synthesize (S)-2,3-epoxysqualene. This comes along with the byproducts of flavin mononucleotide, a hydrogen ion and water. In the final reaction within this pathway,  lanesterol synthase converts (S)-2,3-epoxysqualene to lanosterin. Not pictured in this pathway, lanosterin will eventually be converted to cholesterol, an important part of many functions in the human body.


Bloch Pathway (Cholesterol Biosynthesis) ,Metabolic

The Bloch pathway, named after Konrad Bloch, is the pathway following the mevalonate pathway occurring within the cell to complete cholesterol biosynthesis. Cholesterol is a necessary metabolite that helps create many essential hormones within the human body. This pathway, combined with the mevalonate pathway is one of two ways to biosynthesize cholesterol; the Kandutsch-Russell pathway is an alternative pathway that uses different compounds than the Bloch Pathway beginning after lanosterol. The first three reactions occur in the endoplasmic reticulum. Lanosterol, a compound created through the mevalonate pathway, binds with the enzyme lanosterol 14-alpha demethylase to become 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol. Moving to the next reaction, 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol utilizes the enzyme lanosterol 14-alpha demethylase to create 4,4-dimethyl-14α-formyl-5α-cholesta-8,24-dien-3β-ol. Lanosterol 14-alpha demethylase is used one last time in this pathway, converting 4,4-dimethyl-14α-formyl-5α-cholesta-8,24-dien-3β-ol into 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol. Entering the inner nuclear membrane, 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol is catalyzed by a lamin B receptor to create 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol. Entering the endoplasmic reticulum membrane, 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol, with the help of methyl monooxygenase 1 is converted to 4a-hydroxymethyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol. The enzyme methyl monooxygenase 1 uses 4a-hydroxymethyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol to produce 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol. This reaction is repeated once more, using 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol and methyl monooxygenase 1 to create 4a-carboxy-4b-methyl-5a-cholesta-8,24-dien-3b-ol. Briefly entering the endoplasmic reticulum, 4a-carboxy-4b-methyl-5a-cholesta-8,24-dien-3b-ol then uses sterol-4-alpha-carboxylate-3-dehyrogenase to catalyze into 3-keto-4-methylzymosterol. Back in the endoplasmic reticulum membrane, where the pathway will continue on for the remaining reactions, 3-keto-4-methylzymosterol combines with 3-keto-steroid reductase to create 4a-methylzymosterol. 4a-Methylzymosterol joins the enzyme methylsterol monooxgenase 1 to result in 4a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol. 4a-Hydroxymethyl-5a-cholesta-8,24-dien-3b-ol uses methylsterol monooxygenase 1 to convert to 4a-formyl-5a-cholesta-8,24-dien-3b-ol. 4a-Formyl-5a-cholesta-8,24-dien-3b-ol proceeds to use the same enzyme used in the previous reaction: methylsterol monooxygenase 1, to catalyze into 4a-carboxy-5a-cholesta-8,24-dien-3b-ol. Sterol-4-alpha-carboxylate-3-dehydrogenase is used alongside 4a-carboxy-5a-cholesta-8,24-dien-3b-ol to produce 5a-cholesta-8,24-dien-3-one (also known as zymosterone). Zymosterone (5a-cholesta-8,24-dien-3-one) teams up with 3-keto-steroid reductase to create zymosterol. Zymosterol proceeds to use the enzyme 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase to catalyze into 5a-cholesta-7,24-dien-3b-ol. The compound 5a-cholesta-7,24-dien-3b-ol then joins lathosterol oxidase to convert to 7-dehydrodesmosterol. 7-Dehydrodesmosterol and the enzyme 7-dehydrocholesterol reductase come together to create desmosterol. This brings the pathway to the final reaction, where desmosterol combines with delta(24)-sterol reductase to finally convert to cholesterol.


Kandutsch-Russell Pathway (Cholesterol Biosynthesis),Metabolic

The Kandutsch-Russell pathway is the alternative pathway stemming from the mevalonate pathway completing cholesterol biosynthesis. The Bloch pathway and the Kandutsch-Russell pathway are both key to a functioning human body as cholesterol aids in the development of many important nutrients and hormones, such as vitamin D. Starting in the endoplasmic reticulum, lanosterol is the first compound used in this pathway, and when catalyzed by delta(24)-sterol-reductase, becomes 24,25-dihydrolanosterol. 24,25-Dihydrolanosterol is quickly converted to 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8-en-3b-ol with the help of the enzyme lanosterol 14-alpha demethylase. This same enzyme, lanosterol 14-alpha demethylase, is also responsible for the conversion of 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8-en-3b-ol into 4,4-dimethyl-14a-formyl-5a-cholest-8-en-3b-ol. Lanosterol 14alpha demethylase is used once more here, to push the pathway into the inner nuclear membrane, converting 4,4-dimethyl-14a-formyl-5a-cholest-8-en-3b-ol into 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol. Now located in the inner nuclear membrane, 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol is converted into 4,4-dimethyl-5a-cholesta-8-en-3b-ol through the help of a lamin-b receptor. Entering the endoplasmic reticulum membrane, methylsterol monooxygenase 1 is used to convert 4,4-dimethyl-5a-cholesta-8-en-3b-ol into 4a-hydroxymethyl-4b-methyl-5a-cholesta-8-en-3b-ol. 4a-Hydroxymethyl-4b-methyl-5a-cholesta-8-en-3b-ol then uses methylsterol monooxygenase 1 to become 4a-formyl-4b-methyl-5a-cholesta-8-en-3b-ol. Once again, methylsterol monooxygenase 1 is used to convert 4a-formyl-4b-methyl-5a-cholesta-8-en-3b-ol into 4a-carboxy-4b-methyl-5a-cholesta-8-en-3b-ol. Now using sterol-4-alpha-carboxylate 3-dehydrogenase, 4a-carboxy-4b-methyl-5a-cholesta-8-en-3b-ol is turned into 4a-methyl-5a-cholesta-8-en-3-one. This puts the pathway in the cell membrane, where a 3-keto-steroid reductase is used to convert 4a-methyl-5a-cholesta-8-en-3b-one into  4a-methyl-5a-cholesta-8-en-3-ol. Moving back into the endoplasmic reticulum membrane, methylsterol monooxygenase 1 converts 4a-methyl-5a-cholesta-8-en-3-ol into 4a-hydroxymethyl-5a-cholesta-8-en-3b-ol. Methylsterol monooxygenase is used twice more in this pathway, first converting 4a-hydroxymethyl-5a-cholesta-8-en-3b-ol into 4a-formyl-5a-cholesta-8-en-3b-ol, then converting 4a-formyl-5a-cholesta-8-en-3b-ol into 4a-carboxy-5a-cholesta-8-en-3b-ol. Now using sterol-4-alpha-carboxylate 3 dehydrogenase, 4a-carboxy-5a-cholesta-8-en-3b-ol becomes 5a-cholesta-8-en-3-one and brings the pathway back to the cell membrane. 5a-Cholesta-8-en-3-one teams up with a 3-keto-steroid reductase to create 5a-cholest-8-en-3b-ol. Then, stepping back into the endoplasmic reticulum membrane, 5a-cholest-8-en-3b-ol enlists the help of 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase to produce lathosterol. Lathosterol and lathosterol oxidase work together to make 7-dehydrocholesterol . Finally, 7-dehydrocholesterol partners with 7-dehydrocholesterol reductase to create cholesterol, completing the final step in cholesterol biosynthesis.


Arsenate Detoxification,Metabolic

Arsenate is a compound similar to phosphate, but containing an arsenic atom instead of the phosphorous. As such, it is treated similarly to a phosphate ion. However, if the arsenate replaces inorganic phosphates in glycolysis, it allows glycolysis to proceed, but does not generate ATP, uncoupling glycolysis. It can also bind to lipoic acid in the Krebs cycle, leading to a greater loss of ATP.Arsenate can enter into the cell via aquaporins 7 and 9, as well as facilitated glucose transporter members 1 and 4 of solute carrier family 2, and does so by diffusion.Once inside the cell, the arsenate can be converted to arsenite via the glutathione S-transferase omega-1 enzyme, or it can be converted to ribose-1-arsenate via the purine nucleoside phosphorylase. Ribose-1-arsenate then can spontaneously form arsenite through a reaction involving hydrogen and dihydrolipoate. After arsenite has been formed by either of these methods, arsenite methyltransferase catalyzes its formation into methylarsonate. From here, it forms methylarsonite via the glutathione S-transferase omega-1 enzyme again. The methylarsonite reacts with S-adenosylmethionine, catalyzed by arsenite methyltransferase, in order to become dimethylarsinate. Finally, the compound once again interacts with the glutathione S-transferase omega-1 enzyme to form dimethylarsinous acid, the final compound in this pathway.


Aldosterone from Steroidogenesis ,Physiological

Aldosterone is a hormone produced in the zona glomerulosa of the adrenal cortex.  It's function is to act on the distal convoluted tubule and the collecting duct of the nephron to make them more permeable to sodium to allow for its reuptake (in addition to allowing potassium wasting).  As a result, water follows the sodium back into the body. The water retention contributes to an increased blood volume.  Angiotensin II from the circulation binds to receptors on the zona glomerulosa cell membrane, activating the G protein and triggering a signaling cascade.  The end result is the activation of the steroidogenic acute regulatory (StAR) protein that permits cholesterol uptake into the mitochondria.  From there, cholesterol undergoes a series of reactions in both the mitochondrion and the smooth endoplasmic reticulum (steroidogenesis) where it finally becomes aldosterone.


Pancreas Function - Delta Cell,Physiological

Pancreatic delta cells produce somatostatin which functions to inhibit glucagon, insulin, and itself.  Somatostatin is stored in granules in the delta cell and is released in response to an increase in blood sugar, calcium, and blood amino acids during absorption of a meal. In the process of somatostatin secretion, glucose must first undergo glycolysis in the mitochondrion to increase ATP in the cell. The inside of the alpha cell then becomes electrically positive due to the closure of potassium channels that were inhibited by ATP.  From this closure, the potassium is no longer being shuttled out of the cell, thus depolarizing the cell due to the extra intracellular potassium.  The resulting action potential from the increased membrane potential causes the voltage gate calcium channels to open, creating an influx of calcium into the cell.  This triggers the exocytosis of somatostatin granules from the delta cell.