Abstract
Background: The regulator of G-protein signaling 5 (Rgs5), functions as regulator of G protein coupled receptor (GPCR) including muscarinic receptors, has potentially effect on atrial muscarinic receptor activated I K,Ach current. Objective: To elucidate the effect of regulator of G-protein signaling 5 (Rgs5) on vagal related bradycardia and atrial tachyarrhythmia (ATA) in mice. Methods and Results: In the present study, the Rgs5 knockout (KO) mice had decreased LF/HF ratio in spectral measures of heart rate variability, and provoked dramatically exaggerated bradycardia and significantly (P <0.05) prolonged sinus nodal recovery time in response to carbachol (0.1mg/kg, IP). However, cardiac transgenic of human Rgs5 (Rgs5TG) appeared to confer autonomic balance in terms of LF/HF ratio (1.01 ± 0.17), and found to be resistant to carbachol induced bradycardia (Fig.A 1-2 ). Compared with those from wild-type (WT) mice, Langendorff perfused hearts from Rgs5KO mice had significantly (P <0.01) abbreviated atrial effective refractory periods (ERP) and increased susceptibility of ATA following administration of acetylcholine (1μM). Whereas Rgs5TG hearts showed significant longer ERP and less ATA inducibility than WT groups (P>0.05). In addition, whole patch clamp analyses of single atrial myocytes revealed that the acetylcholine-regulated potassium current (I Kach ) was stronger in Rgs5KO than in WT mice. In atrial myocytes (n=8) from Rgs5TG mice, we found a smaller amplitude of I K,ACh (P>0.05), but the time of activation and deactivation was shorter than in WT mice (P<0.05)(Fig.B 1-4 ). The expression levels of I KACh subunits Kir3.1 and Kir3.4 were similar among three groups (P>0.05). Conclusion: The results of this study indicate that as a critical regulator of parasympathetic activation in the heart, Rgs5 prevents vagal related bradycardia and ATA through negatively regulating the I Kach current.
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