Biochem423 - Signaling pathways

Ideal blood glucose level

5 mM - controlled by pancreas endocrine excretion of insulin and glucagon

Glucagon is released when blood glucose levels are low

Insulin is released when blood glucose levels are high

Glucagon signaling pathway

Glucagon binds to GPCR receptor

GPCR transmits extracullar signals to heterotrimeric G protein

Activates G alpha GTPase activity, exchanging GDP for GTP

Dissociation of alpha and (beta+gamma) subunits, both of which have downstream targets

G alpha activates Adenylate Cyclase which produces cAMP from AMP

AMP binds to PKA regulatory subunits, forming regulatory dimers, while two catalytic PKA monomers are released

Inhibits glycogen synthesis

Activates glycogen degradation and glucose synthesis

Net glucose export

cAMP PKA binding

PKA exists as a stable R₂C₂ tetramer. When cAMP is present, two cAMP molecules bind to each R subunit, causing a conformational change which releases the C subunits.

The Free monomer catalytic subunits are then able to bind and phosphorylate target proteins

RTKs

Receptor Tyrosine Kinase

Transmit extracellular signals by ligand activation of an intrinsic tyrosine kinase function in the receptor

The Insulin Receptor

Tetramer linked together by disulfide bonds. Alpha subunits in the insulin binding region and beta subunits in the cytoplasmic tyrosine kinase domains

Insulin Signaling Pathway

One insulin binds to one receptor, causing dimerization

pY - residues autophosphorylated by insulin receptor.

pY - Docking site for IRS, which is then phosphorylated

p-IRS - Docking site for PI-3K (lipid kinase)

PI-3K (activated) phosphorylates PIP₂ to form PIP₃ which then acts as a docking site for signaling proteins

PIP₃ allows PDK1 to dock and phosphorylate Akt which activates PP1.

Leads to Glucose uptake and glycogen synthesis