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RGS4 attenuates parasympathetic signaling in the sinoatrial node: implications for heart rate regulation
Author(s) -
Cifelli Carlo,
Zhang Hangjun,
Rose Robert Alan,
Backx Peter,
Heximer Scott
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1044.11
Subject(s) - muscarinic acetylcholine receptor , endocrinology , medicine , carbachol , sinoatrial node , atropine , stimulation , heart rate , knockout mouse , sinus rhythm , biology , parasympathetic nervous system , receptor , autonomic nervous system , atrial fibrillation , blood pressure
Parasympathetic signaling in the SAN is mediated by ACh‐dependent stimulation of M2 muscarinic receptors that are coupled to the heterotrimeric G‐protein subunits Giα and GoÎ±ï€ in the SA node. RGS proteins are potent inhibitors of G‐protein signaling. The RGS family members that regulate parasympathetic signaling in pacemaker cells are unknown. We here provide evidence that RGS4 is required for normal inhibition of parasympathetic control of sinus rhythm. Real time RT‐PCR shows that RGS4 is expressed at higher levels in the SAN compared to right atrium. Moreover, the LacZ staining pattern of hearts and right atria from Rgs4tm1Dgen/J knockout/reporter mice indicates robust and selective expression of RGS4 in the SAN. RGS4‐deficient animals showed significantly lower basal heart rates than wild type controls and greater heart rate increases following systemic atropine administration. Lastly, retrograde perfused hearts from RGS4‐deficient mice showed prolonged recovery kinetics following carbachol washout. Taken together these data indicate greater parasympathetic control of heart rate in the knockout strain, and suggest an important role for RGS4 in the normal inhibition of parasympathetic signaling and regulation of sinus rhythm in the mouse heart.