* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download cGMP Intracellular Signal
Survey
Document related concepts
Hedgehog signaling pathway wikipedia , lookup
Phosphorylation wikipedia , lookup
Protein moonlighting wikipedia , lookup
Purinergic signalling wikipedia , lookup
NMDA receptor wikipedia , lookup
Protein phosphorylation wikipedia , lookup
List of types of proteins wikipedia , lookup
Tyrosine kinase wikipedia , lookup
Mitogen-activated protein kinase wikipedia , lookup
VLDL receptor wikipedia , lookup
G protein–coupled receptor wikipedia , lookup
Transcript
cGMP Intracellular Signal • cGMP is made from GTP by the enzyme gaunylyl cyclase. • Atrial natriuretic peptide and nitric oxide function through this Signal. • These are potent vasodilators. • Inhibitors of cGMP phosphodiestrase is sildenafil (Viagra). • The increased cGMP activates cGMP dependent protein kinase (PKG). • This in turn phosphorylates a number of smooth muscle proteins. • This leads to relaxation of smooth muscle cell and vasodilation. Calcium or Phosphatidylinositol • Ionized calcium is an important regulator of many cellular processes, including: • muscle contraction, • secretion, • blood clotting, • enzyme activity and • membrane excitability. • Calcium Metabolism: • Extracellular Ca conc is 5mmol/L. • Ca is restrained from entering the cell and the intracellular conc of free and ionized Ca is very low 0.05-10μmol/L. • Some signal must provide communication between the hormone receptor on the plasma membrane and the intracellular Ca reservoirs. • This is accomplished by products of phosphatidyl inositol metabolism. • Cell surface receptors such as those for: • acetylcholine, • antidiuretic hormone and • α1 – catecholamines • When occupied by these ligands they are potent activators of Phospholipase C. • This involves a specific G protein, which also may activate a calcium channel. • Phospholipase C cleaves Phosphatidyl inositol 4,5 bisphosphate (PIP2) into : • 1. 1,2 Diacyl glycerol(DAG) and • 2. inositol 1,4, 5 triphosphate(IP3). • DAG is a potent activator of protein kinase C. • The activated PKC phosphorylates specific substrates, which then alter physiologic processes. • IP3 liberates stored intracellular Ca from the endoplasmic reticulum. • Ca-Calmodulin complex is formed and this also activate specific kinases which phosphorylates specific substrates, which then alter physiologic processes. • The same G- protein activation also activates a calcium channel and Ca can enter the cell. Enzymes and Proteins regulated by Ca and Calmodulin • • • • • Adenylyl Cyclase Ca –dependent protein kinases. Ca- Mg ATPase Nitric oxide synthase Phosphorylase kinase Insulin Signaling Pathways • Insulin is released in response to hyperglycemia. • Insulin binds to cell surface receptors . • These receptors have intrinsic tyrosine kinase activity. • The receptors are then auto phosphorylated on tyrosine residues. • This initiates a complex series of events. • The phosphorylated receptor then next phosphorylate insulin receptor substrates(IRS 1-4). • These IRS then bind to Src homology domains on the proteins and are involved in different effects of insulin. • Effects of this pathway: • 1. Protein translocation (glucose transporters, insulin receptors) • Enzyme activity (insulin receptor, Phosphatases, phosphodiestrases) • Gene transcription (PEPCK, Glucagon,Glucokinase) JAK STAT Pathway • • • • • Growth hormone Prolactin Erythropoietin Cytokines Activate a tyrosine kinase, but this activity is not an integral part of the receptor. • When the ligand binds to the receptor then the receptor dimerizes and associated cytoplasmic protein kinases such as; Tyk-2, Jak1, Jak2 are phosphorylated. • Jak-P now becomes an active kinase and it then phosphorylates the receptor on tyrosine residue. • The kinases then phosphorylate other cytoplasmic proteins. • One of the cytoplasmic proteins family is called signal transducers and activators of transcription(STAT). • The phosphorylated STAT protein dimerizes and translocates to the nucleus and bind to specific DNA sequence. • The phosphotyrosine residues of the receptor also bind to docking proteins through SH2 • domain. • This result in the activation of other pathways. NF-кB Pathway • This pathway is regulated by Glucocorticoids. • NF-кB factor is composed of two subunits termed p50 and p65. • Normally NF-кB factor is sequestered in the cytoplasm in an inactive form by the inhibitors(IкB). • Extracellular stimuli such as proinflammatory cytokines, reactive oxygen species, and mitogens lead to the activation of IкB kinase complex, called IKK. • IKK phosphorylate inhibitor(IкB). • This causes degradation of inhibitor(IкB). • NF-кB factor is free and it translocates to the nucleus and promote gene transcription. • • • • • NF-кB activators are: Proinflammatory cytokines Bacterial and viral infection Reactive oxygen species Mitogens • Inhibitors of NF-кB: • Glucocorticoid hormones are therapeutically useful agents for the treatment of a variety of inflammatory and immune diseases.. • These actions in part are explained by the inhibition of NF-кB pathway. • Increase the level of inhibitoe • Compete with the Co activators for the receptor. • Directly bind to p65 subunit of NF-kB.