Potential Role of Regulator of G‐Protein Signaling 5 in the Protection of Vagal‐Related Bradycardia and Atrial Tachyarrhythmia

Abstract

BackgroundThe regulator of G‐protein signaling 5 (Rgs5), which functions as the regulator of G‐protein‐coupled receptor (GPCR) including muscarinic receptors, has a potential effect on atrial muscarinic receptor‐activated IKA ch current.Methods and ResultsIn the present study, hearts of Rgs5 knockout (KO) mice had decreased low‐frequency/high‐frequency ratio in spectral measures of heart rate variability. Loss of Rgs5 provoked dramatically exaggerated bradycardia and significantly (P<0.05) prolonged sinus nodal recovery time in response to carbachol (0.1 mg/kg, intraperitoneally). Compared to those from wild‐type (WT) mice, Langendorff perfused hearts from Rgs5 KO mice had significantly (P<0.01) abbreviated atrial effective refractory periods and increased dominant frequency after administration of acetylcholine (ACh; 1 μmol/L). In addition, whole patch clamp analyses of single atrial myocytes revealed that the ACh‐regulated potassium current (IKA ch) was significant increased in the time course of activation and deactivation (P<0.01) in Rgs5 KO, compared to those in WT, mice. To further determine the effect of Rgs5, transgenic mice with cardiac‐specific overexpression of human Rgs5 were found to be resistant to ACh‐related effects in bradycardia, atrial electrophysiology, and atrial tachyarrhythmia (AT).ConclusionThe results of this study indicate that, as a critical regulator of parasympathetic activation in the heart, Rgs5 prevents vagal‐related bradycardia and AT through negatively regulating the IKA ch current.

Progress of Pathogenesis in Pediatric Multifocal Atrial Tachycardia

“…The heart is innervated by the autonomic nervous system, including the sympathetic and parasympathetic nervous systems. The autonomic nervous system plays a key role in the control of heart rate and pathogenesis of multiple types of cardiac arrhythmia (64)(65)(66).…”

Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling

“…RGS2 has been shown to negatively regulate β 2 AR-G i/o signaling in the myocardium; accordingly, downregulation or the absence of RGS2 leads to decreased cardiomyocyte contractile response to βAR stimulation [ 7 ]. Because G i/o is also regulated by RGS5 [ 3 ], and that the loss of RGS5 also predisposes to arrhythmias [ 9 , 10 ], we reasoned that decreased contractility and increased rate of ventricular myocyte arrhythmias following the dual absence of RGS2 and 5 could be due, at least partly, to augmented inhibitory G i/o activity. To test this hypothesis, we compared G i/o activity in freshly isolated cardiomyocytes from WT, Rgs2 KO, Rgs5 KO and Rgs2/5 dbKO male mice.…”

“…Besides having mildly elevated or reduced resting blood pressure, mice lacking RGS2 or RGS5 alone do not show any baseline cardiac phenotype except when subjected to experimental stressors including pressure overload and cardiac pacing [ 12 , 26 , 32 , 33 ]. Previous studies have also reported that the absence of RGS2 or 5 increases the incidence of atrial tachyarrhythmia induced with muscarinic receptor stimulation [ 34 , 35 ], and ventricular tachyarrhythmia in response to programmed electrical stimulation of isolated hearts [ 9 , 10 ]. Our findings now show that the dual absence of RGS2 and 5 causes unprovoked left ventricular dilatation without cardiomyocyte hypertrophy and independently of the associated baseline blood pressure elevation.…”

“…In cardiomyocytes, the overexpression of RGS2 suppresses agonist-induced, β 2 AR-mediated G αi signaling, a pathway implicated in ventricular arrhythmia, heart failure, and hypertension [ 7 ]. Similar to RGS2, RGS5 has also been shown to display relevance in proper cardiac function, specifically in the repolarization phase of cardiac contraction [ 9 , 10 ], hypertrophy and fibrosis [ 11 , 12 ], and maintenance of blood pressure homeostasis [ 13 ]. Thus, RGS2 and 5 seem to play overlapping roles in the cardiovascular system.…”

Ras Association (RalGDS/AF-6) Domain Family

“…Similarly, in RGS5 overexpressing mouse hearts, cardiomyocytes are protected from apoptosis during ischemic injury through inhibition of JNK1/2 and p38 signaling ). In addition, RGS5 regulates parasympathetic activation in the heart, heart rate, and rhythm; this is effected by negatively regulating atrial muscarinic receptoractivated potassium channels (I KAch ) (Qin et al 2016).…”