Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 7, Pages E932-E941Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1517181113
Keywords
heart rate regulation; sick sinus syndrome; heart block; GIRK4; Ca(v)1.3
Categories
Funding
- Agence Nationale pour la Recherche (ANR) [ANR-06-PHISIO-004-01, ANR-09-GENO-034, ANR-2010-BLAN-1128-01]
- Austrian Science Fund [FWF F44020]
- NIH [R01 HL087120-A2, R01 HL105550]
- CavNet, a Research Training Network through the European Union Research Programme (6FP) [MRTN-CT-2006-035367]
- Fondation Lefoulon-Delalande (Paris)
- ANR [ANR-11-LABX-0015]
- Fondation de France, Paris [Cardiovasc 2008002730]
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Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies sick sinus syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Ca(v)1.3 Ca2+ channels (Ca(v)1.3(-/-)) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K+ channel (I-KACh) could rescue SSS and heart block in Cav1.3(-/-)mice. We found that genetic inactivation of I-KACh abolished SSS symptoms in Cav1.3(-/-) mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of I-KACh either in Cav1.3(-/-) mice or following selective inhibition of Ca(v)1.3-mediated L-type Ca2+ (I-Ca,I- L) current in vivo. Ablation of I-KACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from I-KACh suppression achieved by gene therapy or selective pharmacological inhibition.
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