title: G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block.
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 Ca(2+) 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 Ca(2+) (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.
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France; pietro.mesirca@igf.cnrs.fr matteo.mangoni@igf.cnrs.fr.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mesirca
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bidaud
authors.affiliation: INSERM, UMR_S1087, l'Institut du Thorax, F-44007 Nantes, France;
authors.forename: François
authors.initials: F
authors.lastname: Briec
authors.affiliation: INSERM, UMR_S1087, l'Institut du Thorax, F-44007 Nantes, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Evain
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France;
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Torrente
authors.affiliation: INSERM, UMR_S1087, l'Institut du Thorax, F-44007 Nantes, France; Université de Nantes, F-44007 Nantes, France;
authors.forename: Khai
authors.initials: K
authors.lastname: Le Quang
authors.affiliation: INSERM U661, F-34094 Montpellier, France;
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Leoni
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France;
authors.forename: Matthias
authors.initials: M
authors.lastname: Baudot
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France;
authors.forename: Laurine
authors.initials: L
authors.lastname: Marger
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France;
authors.forename: Antony
authors.initials: A
authors.lastname: Chung You Chong
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France;
authors.forename: Joël
authors.initials: J
authors.lastname: Nargeot
authors.affiliation: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, A-6020 Innsbruck, Austria;
authors.forename: Joerg
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 554557;
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.affiliation: INSERM, UMR_S1087, l'Institut du Thorax, F-44007 Nantes, France; Université de Nantes, F-44007 Nantes, France; CNRS UMR 6291, l'Institut du Thorax, F-44007 Nantes, France; Centre Hospitalier Universitaire Nantes, F-44007 Nantes, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, Laboratory of Excellence in Ion Channel Science and Therapeutics, UMR-5203, CNRS, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université de Montpellier, F-34094 Montpellier, France; pietro.mesirca@igf.cnrs.fr matteo.mangoni@igf.cnrs.fr.
authors.forename: Matteo E
authors.initials: ME
authors.lastname: Mangoni
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006327:Heart Block / Q000188:drug therapy*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012804:Sick Sinus Syndrome / Q000188:drug therapy*
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D019204:GTP-Binding Proteins
keywords: Cav1.3; GIRK4; heart block; heart rate regulation; sick sinus syndrome
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