Download cGMP Intracellular Signal

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
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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
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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.
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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.