RGS6, but not RGS4, is the dominant regulator of G protein signaling (RGS) modulator of the parasympathetic regulation of mouse heart rate

J Biol Chem. 2014 Jan 24;289(4):2440-9. doi: 10.1074/jbc.M113.520742. Epub 2013 Dec 6.


Parasympathetic activity decreases heart rate (HR) by inhibiting pacemaker cells in the sinoatrial node (SAN). Dysregulation of parasympathetic influence has been linked to sinus node dysfunction and arrhythmia. RGS (regulator of G protein signaling) proteins are negative modulators of the parasympathetic regulation of HR and the prototypical M2 muscarinic receptor (M2R)-dependent signaling pathway in the SAN that involves the muscarinic-gated atrial K(+) channel IKACh. Both RGS4 and RGS6-Gβ5 have been implicated in these processes. Here, we used Rgs4(-/-), Rgs6(-/-), and Rgs4(-/-):Rgs6(-/-) mice to compare the relative influence of RGS4 and RGS6 on parasympathetic regulation of HR and M2R-IKACh-dependent signaling in the SAN. In retrogradely perfused hearts, ablation of RGS6, but not RGS4, correlated with decreased resting HR, increased heart rate variability, and enhanced sensitivity to the negative chronotropic effects of the muscarinic agonist carbachol. Similarly, loss of RGS6, but not RGS4, correlated with enhanced sensitivity of the M2R-IKACh signaling pathway in SAN cells to carbachol and a significant slowing of M2R-IKACh deactivation rate. Surprisingly, concurrent genetic ablation of RGS4 partially rescued some deficits observed in Rgs6(-/-) mice. These findings, together with those from an acute pharmacologic approach in SAN cells from Rgs6(-/-) and Gβ5(-/-) mice, suggest that the partial rescue of phenotypes in Rgs4(-/-):Rgs6(-/-) mice is attributable to another R7 RGS protein whose influence on M2R-IKACh signaling is masked by RGS4. Thus, RGS6-Gβ5, but not RGS4, is the primary RGS modulator of parasympathetic HR regulation and SAN M2R-IKACh signaling in mice.

Keywords: G Proteins; GIRK/Kir3; Gene Knockout; Heart; Muscarinic; Patch Clamp Electrophysiology; Potassium Channels; RGS Proteins; Sinoatrial Node.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbachol / pharmacology
  • Cardiotonic Agents / pharmacology
  • GTP-Binding Protein beta Subunits / genetics
  • GTP-Binding Protein beta Subunits / metabolism
  • Heart Rate / drug effects
  • Heart Rate / physiology*
  • Mice
  • Mice, Knockout
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Parasympathetic Nervous System / metabolism*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Receptor, Muscarinic M2 / genetics
  • Receptor, Muscarinic M2 / metabolism
  • Sinoatrial Node / cytology
  • Sinoatrial Node / metabolism*


  • Cardiotonic Agents
  • GTP-Binding Protein beta Subunits
  • Muscle Proteins
  • Potassium Channels
  • RGS Proteins
  • Receptor, Muscarinic M2
  • Rgs6 protein, mouse
  • RGS4 protein
  • Carbachol