Controlling Parasympathetic Regulation of Heart Rate: A Gatekeeper Role for RGS Proteins in the Sinoatrial Node

Abstract

Neurotransmitters released from sympathetic and parasympathetic nerve terminals in the sinoatrial node (SAN) exert their effects via G-protein-coupled receptors. Integration of these different G-protein signals within pacemaker cells of the SAN is critical for proper regulation of heart rate and function. For example, excessive parasympathetic signaling can be associated with sinus node dysfunction (SND) and supraventricular arrhythmias. Our previous work has shown that one member of the regulator of G-protein signaling (RGS) protein family, RGS4, is highly and selectively expressed in pacemaker cells of the SAN. Consistent with its role as an inhibitor of parasympathetic signaling, RGS4-knockout mice have reduced basal heart rates and enhanced negative chronotropic responses to parasympathetic agonists. Moreover, RGS4 appears to be an important part of SA nodal myocyte signaling pathways that mediate G-protein-coupled inwardly rectifying potassium channel (GIRK) channel activation/deactivation and desensitization. Since RGS4 acts immediately downstream of M2 muscarinic receptors, it is tempting to speculate that RGS4 functions as a master regulator of parasympathetic signaling upstream of GIRKs, HCNs, and L-type Ca(2+) channels in the SAN. Thus, loss of RGS4 function may lead to increased susceptibility to conditions associated with increased parasympathetic signaling, including bradyarrhythmia, SND, and atrial fibrillation.

Keywords: GIRK channels; RGS protein; bradyarrhythmia; parasympathetic signaling; sinoatrial node.

Figure 1

Modeling parasympathetic signaling pathways in pacemaker cells of the SAN in the presence (A) and absence (B) of RGS4 function. Note the potential for RGS4 to act as a master upstream regulator of the primary effectors of the M2 muscarinic receptor (GIRK channels, and adenylyl cyclase). (A) In the model where RGS4 is functional, Gα_i signaling is attenuated resulting in decreased GIRK channel activity and increased cAMP concentrations that can directly stimulate increased HCN4 channel activity and indirectly (via PKA activation) increases Ca_V channel activity. (B) In the model where RGS4 function is absent Gα_i signaling is increased resulting in increased GIRK channel activity and decreased cAMP concentrations. This condition is expected to result in lower HCN4 and Ca_V channel activity.