Figure 1.

Compartmentalized cAMP signaling by different receptors in adult ventricular myocytes. (A) Distribution of receptors to specific locations, along with targeted PDE activity, buffering of cAMP by protein kinase A (PKA), and physical barriers to diffusion allows for generation of local pools of cAMP. While β₁ARs are expressed throughout the cell, β₂ARs are confined to the plasma membrane lining the transverse tubules. β₂ARs are also found primarily in caveolar lipid raft domains of the plasma membrane; β₁ARs can be found in caveolar as well as non-caveolar membrane domains; and EPRs are found primarily in non-caveolar membrane domains. (B) β₁ARs and β₂ARs form signaling complexes with L-type Ca²⁺ channels (LTCCs), which are found in dyadic clefts. Both of these receptors produce cAMP that can regulate LTCCs as well as ryanodine receptors (RyRs) within this restricted space. (C) β₁ARs are also able to contribute to a distinct pool of cAMP that regulates the activity of the sarco/endoplasmic reticulum ATPase (SERCA) via PKA-dependent phosphorylation of phospholamban (PLB) (D) E type prostaglandin receptors (EPRs) contribute to a pool of cAMP that does not affect PKA regulation of LTCCs or PLB, which are involved in excitation-contraction coupling, although it can produce cardioprotective effects. (E) An intracellular pool of β₁ARs found in the SR have also been reported to produce a localized response that leads to phosphorylation of PLB and regulation of SERCA.