Modeling cAMP-cGMP Crosstalk in the Cardiac Myocyte

Abstract

While the role of nitric oxide (NO) in regulating cardiac function through vascular smooth muscle relaxation has been characterized over the past 15 years, NO's effects in the cardiac myocyte have yet to be resolved. The addition of NO to these cells has been reported to cause a biphasic response; NO either increases or decreases cardiac contractility depending on its concentration. Proposed mechanisms for this response include a number of factors, ranging from direct nitrosylation of the ryanodine receptor by NO to modulation of the beta-adrenergic signaling pathway by NO-induced cGMP. This latter interaction is supported by experimental data showing a concomitant biphasic response of the L-type calcium current.In order to elucidate the mechanisms underlying the biphasic response of the L-type calcium current to NO, we have developed a model combining descriptions of cAMP production via the beta-adrenergic signaling pathway and cGMP production via a NO signaling pathway. The cAMP-cGMP crosstalk model couples the production of cGMP by guanylyl cyclase to the beta-adrenergic signaling pathway via cGMP-activated and cGMP-inhibited cAMP phosphodiesterases (PDEs.) Integrative regulation of cAMP concentration will ultimately regulate the L-type calcium current, via altered activation of protein kinase A.We hypothesized that the opposing behavior of these two cGMP-regulated cAMP PDEs leads to the biphasic effects on L-type calcium current seen experimentally.To test this hypothesis, a model was formulated from existing models describing cGMP synthesis and beta-adrenergic control of L-type calcium current. These two pathway models were coupled using enzyme kinetic data describing the PDEs. Simulations from the model combining these two pathways show that the interplay between these two cGMP-regulated cAMP PDEs gives rise to the biphasic response of the L-type calcium current. Supported by R33HL87345.