22.6 : cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA, dissociating the catalytic subunits from the regulatory subunit. Activated PKA can now phosphorylate serine/threonine residues of downstream target proteins and stimulate them to produce an appropriate cellular response. PKA can generate distinct responses in different cells by activating specific target proteins, even when stimulated by the same extracellular ligand.

In liver and muscle cells, epinephrine-bound G protein-coupled receptors (GPCR) cause a rise in cAMP levels. The increased cAMP further activates PKA to promote glucose mobilization in two ways.

1. It phosphorylates glycogen phosphorylase kinase (GPK) and activates it. GPK further phosphorylates and activates glycogen phosphorylase (GP), which catalyzes the breakdown of glycogen into glucose 1-phosphate.
2. PKA also phosphorylates and inhibits glycogen synthase (GS) and prevents glycogen synthesis.

In addition, PKA phosphorylates an inhibitor of phosphoprotein phosphatase (IP). The phosphorylated IP binds and blocks phosphoprotein phosphatase, preventing it from dephosphorylating GPK, GP, or GS.

Once the extracellular stimulus is removed, cAMP levels decrease, switching off PKA. Inactive PKA cannot activate phosphoprotein phosphatase inhibitors. Thus, phosphoprotein phosphatase becomes active and removes phosphates from enzymes involved in glycogen degradation and synthesis. The dephosphorylation promotes glycogen synthesis and prevents glucose mobilization.

Contrarily to liver and muscle cells, epinephrine-induced activation of PKA in adipose cells leads to phosphorylation and activation of the enzyme lipase. The activated enzyme breaks down stored triglycerides to produce free fatty acids, which are used as an energy source by the kidney, heart, and muscle cells.