ActivationofcAMPdependentproteinkinase,PKA

G-protein coupled receptors (GPCRs) are one of the largest gene families of signaling proteins. Residing in the plasma membrane with seven transmembrane domains, GPCRs respond to extracellular stimuli that include catecholamine neurotransmitters, neuropeptides, larger protein hormones, lipids, nucleotides and other biological molecules. When a GPCR binds its extracellular ligand, it interacts with a G-protein to transduce a signal across the membrane into the cellular interior. G-proteins are a heterotrimeric complex containing a Ga subunit with GTPase activity, as well as b and g subunits. Ga can exist in an active state and an inactive state. Ga in the off state has GDP bound and does not activate downstream signaling molecules. When a GPCR is activated by ligand, it stimulates Ga subunits to bind GTP instead of GDP and become active, dissociating from the receptor and from the b/g subunits to activate downstream signaling factors like the enzyme adenylyl cyclase that synthesizes cyclic-AMP (cAMP) from ATP. Ga turns itself back off again with its intrinsic GTPase activity, hydrolyzing GTP to GDP to become inactive again.Activated G proteins interact with downstream signaling factors to alter the production of second messenger signaling molecules like inositolphosphates, calcium and cAMP. GPCRs that activate the Gi class of Ga subunits inhibit cAMP production and GPCRs that activate the Gs class of Ga subunits activate cAMP production. cAMP in turn activates the cAMP-dependent protein kinase, protein kinase A (PKA). PKA is a tetramer composed of catalytic subunits and regulatory subunits that repress the catalytic units when they are bound together. The regulatory subunits bind cAMP when it is present and release the catalytic units, releasing their inhibition of the catalytic subunits as well. The catalytic subunits of PKA when they are released and active phosphorylate target substrate proteins on serine and threonine residues, altering the activity of the modified protein and creating a cellular response to the extracellular stimulus acting on the GPCR.The PKA activation pathway is an example of a signal transduction cascade, in which tying several signaling events together amplifies the original signal in the cell. For each GPCR molecule that is activated, many G-proteins can be activated, and each active G protein can synthesize many cAMP molecules, continuing the cascade to PKA and further downstream. One of the roles of PKA that was first studied was the regulation of glycogen metabolism. When epinephrine binds to its receptor in liver, it activates cAMP production and PKA activation. One substrate of PKA is phosphorylase kinase, which is activated phosphorylation and is part of the signaling cascade that mobilizes glycogen into glucose to provide energy that fuels the response to epinephrine. Another substrate of PKA is glycogen synthase, which is turned off by PKA phosphorylation. PKA also participates in many other signaling pathways, integrating the key signaling intermediary cAMP with a wide range of biological responses

Contributor: Glenn Croston, PhD.

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