Mechanism for cAMP Overshoot in Ventricular Myocytes Following β1-Adrenergic Stimulation

Abstract

The sympathetic nervous system (SNS) plays a fundamental role in regulating cardiac function through activation of β-adrenergic receptors (β-ARs) and the subsequent increase in cAMP production. However, SNS input to the heart can sometimes lead to arrhythmias. In particular, certain motifs of SNS input have been shown to trigger large transient increases (i.e., overshoots) of cAMP concentration in ventricular cells, which have the potential to induce ectopic beats. The specific conditions promoting such proarrhythmic activity are unclear. Stimulation of β1-ARs leads to a cascade of intracellular reactions: adenylyl cyclase activated by stimulatory G-protein increases production of cAMP, which activates PKA; PKA then phosphorylates many targets, including calcium and potassium channels, ryanodine receptors, and troponin, as well as β1-ARs. Detailed computational models have been used to describe the β1-adrenergic signaling process, but the complexity of these models makes it difficult to uncover the mechanisms underlying subtle behavior, such as cAMP overshoots. Here, we exploit multiple timescales to reduce the 16-variable adrenergic signaling component of the Soltis-Saucerman model to a system of two differential equations for cAMP and active β1-AR concentrations. We then analyze the reduced model to reveal the mechanism underlying cAMP overshoot in response to β1-AR activation and identify parameters that determine the magnitude of the overshoot. Our results allow us to make predictions for how pharmacological methods can be used to deter the potential proarrhythmic effects of SNS input to the heart.