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

doi:10.1073/pnas.1517181113

G protein-gated I_KACh 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

Pharmacology

Research output: Contribution to journal › Article › peer-review

45 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 Ca_v1.3 Ca²⁺ channels (Ca_v1.3^-/-) 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 Ca_v1.3^-/- mice. We found that genetic inactivation of I_KACh abolished SSS symptoms in Ca_v1.3^-/- 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 Ca_v1.3^-/- mice or following selective inhibition of Ca_v1.3-mediated L-type Ca²⁺ (I_Ca,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 IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

Original language	English (US)
Pages (from-to)	E932-E941
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1517181113
State	Published - Feb 16 2016

Bibliographical note

Funding Information:
We thank former Prof. Denis Escande (Institut du Thorax) for input and support. We also thank Prof. Philippe Chevalier (Centre Hospitalier Universitaire) for critical reading of the manuscript. We are indebted to the staff of the RAM (Réseau des Animaleries de Montpellier) animal facility of the University of Montpellier for managing mouse lines. The project was supported Agence Nationale pour la Recherche (ANR) Grants ANR-06-PHISIO-004-01, ANR-09-GENO-034, and ANR-2010-BLAN-1128-01 (to M.E.M.); by the Fondation de France, Paris (Cardiovasc 2008002730 to J.N.); by the Austrian Science Fund (FWF F44020 to J.S.); and by NIH Grants R01 HL087120-A2 (to M.E.M.) and R01 HL105550 (to K.W.). P.M. and A.G.T. were supported by the CavNet, a Research Training Network funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. received a postdoctoral fellowship from the Fondation Lefoulon-Delalande (Paris). The Institut de Genomique Fonctionnelle group is a member of the Laboratory of Excellence "Ion Channel Science and Therapeutics" supported by a grant from the ANR (ANR-11-LABX-0015).

Keywords

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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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 I_KACh 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

Mesirca, P, Bidaud, I, Briec, F, Evain, S, Torrente, AG, Le Quang, K, Leoni, AL, Baudot, M, Marger, L, Chong, ACY, Nargeot, J, Striessnig, J, Wickman, K, Charpentier, F & Mangoni, ME 2016, 'G protein-gated I_KACh 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, vol. 113, no. 7, pp. E932-E941. https://doi.org/10.1073/pnas.1517181113

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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.",

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note = "Funding Information: We thank former Prof. Denis Escande (Institut du Thorax) for input and support. We also thank Prof. Philippe Chevalier (Centre Hospitalier Universitaire) for critical reading of the manuscript. We are indebted to the staff of the RAM (R{\'e}seau des Animaleries de Montpellier) animal facility of the University of Montpellier for managing mouse lines. The project was supported Agence Nationale pour la Recherche (ANR) Grants ANR-06-PHISIO-004-01, ANR-09-GENO-034, and ANR-2010-BLAN-1128-01 (to M.E.M.); by the Fondation de France, Paris (Cardiovasc 2008002730 to J.N.); by the Austrian Science Fund (FWF F44020 to J.S.); and by NIH Grants R01 HL087120-A2 (to M.E.M.) and R01 HL105550 (to K.W.). P.M. and A.G.T. were supported by the CavNet, a Research Training Network funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. received a postdoctoral fellowship from the Fondation Lefoulon-Delalande (Paris). The Institut de Genomique Fonctionnelle group is a member of the Laboratory of Excellence {"}Ion Channel Science and Therapeutics{"} supported by a grant from the ANR (ANR-11-LABX-0015).",

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T1 - G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

AU - Mesirca, Pietro

AU - Bidaud, Isabelle

AU - Briec, François

AU - Evain, Stéphane

AU - Torrente, Angelo G.

AU - Le Quang, Khai

AU - Leoni, Anne Laure

AU - Baudot, Matthias

AU - Marger, Laurine

AU - Chong, Antony Chung You

AU - Nargeot, Joël

AU - Striessnig, Joerg

AU - Wickman, Kevin

AU - Charpentier, Flavien

AU - Mangoni, Matteo E.

N1 - Funding Information: We thank former Prof. Denis Escande (Institut du Thorax) for input and support. We also thank Prof. Philippe Chevalier (Centre Hospitalier Universitaire) for critical reading of the manuscript. We are indebted to the staff of the RAM (Réseau des Animaleries de Montpellier) animal facility of the University of Montpellier for managing mouse lines. The project was supported Agence Nationale pour la Recherche (ANR) Grants ANR-06-PHISIO-004-01, ANR-09-GENO-034, and ANR-2010-BLAN-1128-01 (to M.E.M.); by the Fondation de France, Paris (Cardiovasc 2008002730 to J.N.); by the Austrian Science Fund (FWF F44020 to J.S.); and by NIH Grants R01 HL087120-A2 (to M.E.M.) and R01 HL105550 (to K.W.). P.M. and A.G.T. were supported by the CavNet, a Research Training Network funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. received a postdoctoral fellowship from the Fondation Lefoulon-Delalande (Paris). The Institut de Genomique Fonctionnelle group is a member of the Laboratory of Excellence "Ion Channel Science and Therapeutics" supported by a grant from the ANR (ANR-11-LABX-0015).

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N2 - 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.

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KW - Ca1.3

KW - GIRK4

KW - Heart block

KW - Heart rate regulation

KW - Sick sinus syndrome

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