cgmp intracellular signal cgmp is made from gtp by the enzyme gaunylyl cyclase. atrial natriuretic...
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.