Figure 1.

Alternate modes of GPCR signaling via cAMP and the phosphoproteome. The first pool of cAMP production takes place at the cell membrane after activation of G_s by the agonist-bound receptors (step 1). This cAMP response is usually short-lived because of the action of phosphodiesterases and rapid receptor desensitization, followed by receptor endocytosis (step 2). Eventually, internalized receptors induce a second pool of cAMP generation that originates from ligand–GPCR complexes in endosomes. Each location-derived cAMP pool triggers a unique phospho-proteomic response inside the cell. The phosphoproteome heat map is from Tsvetanova et al. (8). AC, adenylate cyclase; GPCR, G protein–coupled receptor.