G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

Pietro Mesirca, Isabelle Bidaud, François Briec, Stéphane Evain, Angelo G. Torrente, Khai Le Quang, Anne Laure Leoni, Matthias Baudot, Laurine Marger, Antony Chung You Chong, Joël Nargeot, Joerg Striessnig, Kevin Wickman, Flavien Charpentier, Matteo E. Mangoni

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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 Cav1.3 Ca2+ channels (Cav1.3-/-) 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 (IKACh) could rescue SSS and heart block in Cav1.3-/- mice. We found that genetic inactivation of IKACh 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 IKACh either in Cav1.3-/- mice or following selective inhibition of Cav1.3-mediated L-type Ca2+ (ICa,L) current in vivo. Ablation of IKACh 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 IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

Original languageEnglish (US)
Pages (from-to)E932-E941
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number7
DOIs
StatePublished - Feb 16 2016

Keywords

  • Ca1.3
  • GIRK4
  • Heart block
  • Heart rate regulation
  • Sick sinus syndrome

Fingerprint Dive into the research topics of 'G protein-gated I<sub>KACh</sub> channels as therapeutic targets for treatment of sick sinus syndrome and heart block'. Together they form a unique fingerprint.

  • Cite this

    Mesirca, P., Bidaud, I., Briec, F., Evain, S., Torrente, A. G., Le Quang, K., Leoni, A. L., Baudot, M., Marger, L., Chong, A. C. Y., Nargeot, J., Striessnig, J., Wickman, K., Charpentier, F., & Mangoni, M. E. (2016). G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block. Proceedings of the National Academy of Sciences of the United States of America, 113(7), E932-E941. https://doi.org/10.1073/pnas.1517181113