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Compartmentation of cAMP Signaling in Cardiac Myocytes: A Computational Study

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio

Correspondence: Address reprint requests to Robert D. Harvey, Dept. of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-5521; Fax: 216-368-3952; E-mail: rdh3{at}case.edu.

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 ß₁-adrenergic receptor (ß₁AR) and M₂ 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 ß₁ARs and M₂Rs, 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 G_i, and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high (1 µM) and only modestly stimulated by ß₁AR activation (2 µM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A (100 nM to 2 µM); 2), M₂R activation strongly reduces the ß₁AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak ß₁AR 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.

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