Compartmentation of cAMP signaling in cardiac myocytes: A computational study

Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In this study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of beta(1)-adrenergic receptor (beta(1)AR) and M-2 muscarinic receptor (M2R) activation involve compartmentation of cAMP. A model consisting of two submembrane (caveolar and extracaveolar) microdomains and one bulk cytosolic domain was created using published information on the location of beta(1)ARs and M(2)Rs, as well as the location of stimulatory (G(s)) and inhibitory (G(i)) G-proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by Gi, and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high (similar to 1 mu M) and only modestly stimulated by beta(1)AR activation (similar to 2 mM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A (similar to 100 nM to similar to 2 mu M); 2), M2R activation strongly reduces the beta(1)AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak beta(1)AR stimulation, M2R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M2R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling.