CAMP-dependent Pathway - Mechanism

Mechanism

G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins that respond to a variety of extracellular stimuli. Each GPCR binds to and is activated by a specific ligand stimulus that ranges in size from small molecule catecholamines, lipids, or neurotransmitters to large protein hormones. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex. The G_s alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is released from the complex.

In a cAMP-dependent pathway, the activated G_s alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). Increases in concentration of the second messenger cAMP may lead to the activation of

• cyclic nucleotide-gated ion channels
• exchange proteins activated by cAMP (EPAC) such as RAPGEF3
• an enzyme called protein kinase A (PKA).

The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Once PKA is activated, it phosphorylates a number of other proteins including:

• enzymes that convert glycogen into glucose
• enzymes that promote muscle contraction in the heart leading to an increase in heart rate
• transcription factors, which regulate gene expression

Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP-dependent pathway may be achieved through formation of a multiprotein complex that includes the GPCR, adenylyl cyclase, and the effector protein.