Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation

Pietro Mesirca; Jacqueline Alig; Angelo G. Torrente; Jana Christina Müller; Laurine Marger; Anne Rollin; Claire Marquilly; Anne Vincent; Stefan Dubel; Isabelle Bidaud; Anne Fernandez; Anika Seniuk; Birgit Engeland; Jasmin Singh; Lucile Miquerol; Heimo Ehmke; Thomas Eschenhagen; Joel Nargeot; Kevin Wickman; Dirk Isbrandt; Matteo E. Mangoni

doi:10.1038/ncomms5664

Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation

Pietro Mesirca, Jacqueline Alig, Angelo G. Torrente, Jana Christina Müller, Laurine Marger, Anne Rollin, Claire Marquilly, Anne Vincent, Stefan Dubel, Isabelle Bidaud, Anne Fernandez, Anika Seniuk, Birgit Engeland, Jasmin Singh, Lucile Miquerol, Heimo Ehmke, Thomas Eschenhagen, Joel Nargeot, Kevin Wickman, Dirk IsbrandtMatteo E. Mangoni

Pharmacology

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

64 Scopus citations

Abstract

The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (I f) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific I f silencing caused altered [Ca²⁺] i release and Ca ²⁺ handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of I f silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in I f-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

Original language	English (US)
Article number	4664
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5664
State	Published - Aug 21 2014

Bibliographical note

Funding Information:
We thank I. Hermans-Borgmeyer for transgenic services, K. Sauter for technical assistance and the teams of the UKE animal facility (Hamburg) of the RAM animal facility (Montpellier) for animal care. We also thank N. Lamb for helpful discussions. The project was supported by the Agence Nationale pour la Recherche grant ANR-06-PHISIO-004-01, ANR-2010-BLAN-1128-01, ANR-09-GENO-034 and ANR-13-BSV1-0023-02, the NIH R01HL087120-A2 grant (M.M.), the NIH R01HL105550 (K.W.), the Fondation de France grant 2008002730 (J.N.), the Fondation pour la Recherche Medicale grant DPC20111122986 (A.F.), the Deutsche For-schungsgemeinschaft grant IS63/1–1/2 (D.I. and H.E), IS63/3-1/2 (D.I.), and DFG FOR 604 and Es 88/10-1 (T.E.). P.M. was supported by the CavNet, a Research Training Network (RTN) funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. is a recipient of a postdoctoral fellowship by the Fondation Lefoulon-Delalande. We also thank the Montpellier RIO Imaging facility and their financing bodies. The IGF group is a member of the Laboratory of Excellence ) Ion Channel Science and Therapeutics * supported by a grant from ANR (ANR-11-LABX-0015).

UN SDGs

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

Access

10.1038/ncomms5664

OpenUrl availability

Full text

Cite this

Mesirca, P., Alig, J., Torrente, A. G., Müller, J. C., Marger, L., Rollin, A., Marquilly, C., Vincent, A., Dubel, S., Bidaud, I., Fernandez, A., Seniuk, A., Engeland, B., Singh, J., Miquerol, L., Ehmke, H., Eschenhagen, T., Nargeot, J., Wickman, K., ... Mangoni, M. E. (2014). Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nature communications, 5, Article 4664. https://doi.org/10.1038/ncomms5664

Mesirca, P, Alig, J, Torrente, AG, Müller, JC, Marger, L, Rollin, A, Marquilly, C, Vincent, A, Dubel, S, Bidaud, I, Fernandez, A, Seniuk, A, Engeland, B, Singh, J, Miquerol, L, Ehmke, H, Eschenhagen, T, Nargeot, J, Wickman, K, Isbrandt, D & Mangoni, ME 2014, 'Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation', Nature communications, vol. 5, 4664. https://doi.org/10.1038/ncomms5664

@article{89a05ff58fb4488d948a202344df3bcb,

title = "Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation",

abstract = "The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (I f) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific I f silencing caused altered [Ca2+] i release and Ca 2+ handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of I f silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in I f-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.",

author = "Pietro Mesirca and Jacqueline Alig and Torrente, {Angelo G.} and M{\"u}ller, {Jana Christina} and Laurine Marger and Anne Rollin and Claire Marquilly and Anne Vincent and Stefan Dubel and Isabelle Bidaud and Anne Fernandez and Anika Seniuk and Birgit Engeland and Jasmin Singh and Lucile Miquerol and Heimo Ehmke and Thomas Eschenhagen and Joel Nargeot and Kevin Wickman and Dirk Isbrandt and Mangoni, {Matteo E.}",

note = "Funding Information: We thank I. Hermans-Borgmeyer for transgenic services, K. Sauter for technical assistance and the teams of the UKE animal facility (Hamburg) of the RAM animal facility (Montpellier) for animal care. We also thank N. Lamb for helpful discussions. The project was supported by the Agence Nationale pour la Recherche grant ANR-06-PHISIO-004-01, ANR-2010-BLAN-1128-01, ANR-09-GENO-034 and ANR-13-BSV1-0023-02, the NIH R01HL087120-A2 grant (M.M.), the NIH R01HL105550 (K.W.), the Fondation de France grant 2008002730 (J.N.), the Fondation pour la Recherche Medicale grant DPC20111122986 (A.F.), the Deutsche For-schungsgemeinschaft grant IS63/1–1/2 (D.I. and H.E), IS63/3-1/2 (D.I.), and DFG FOR 604 and Es 88/10-1 (T.E.). P.M. was supported by the CavNet, a Research Training Network (RTN) funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. is a recipient of a postdoctoral fellowship by the Fondation Lefoulon-Delalande. We also thank the Montpellier RIO Imaging facility and their financing bodies. The IGF group is a member of the Laboratory of Excellence ) Ion Channel Science and Therapeutics * supported by a grant from ANR (ANR-11-LABX-0015).",

year = "2014",

month = aug,

day = "21",

doi = "10.1038/ncomms5664",

language = "English (US)",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation

AU - Mesirca, Pietro

AU - Alig, Jacqueline

AU - Torrente, Angelo G.

AU - Müller, Jana Christina

AU - Marger, Laurine

AU - Rollin, Anne

AU - Marquilly, Claire

AU - Vincent, Anne

AU - Dubel, Stefan

AU - Bidaud, Isabelle

AU - Fernandez, Anne

AU - Seniuk, Anika

AU - Engeland, Birgit

AU - Singh, Jasmin

AU - Miquerol, Lucile

AU - Ehmke, Heimo

AU - Eschenhagen, Thomas

AU - Nargeot, Joel

AU - Wickman, Kevin

AU - Isbrandt, Dirk

AU - Mangoni, Matteo E.

N1 - Funding Information: We thank I. Hermans-Borgmeyer for transgenic services, K. Sauter for technical assistance and the teams of the UKE animal facility (Hamburg) of the RAM animal facility (Montpellier) for animal care. We also thank N. Lamb for helpful discussions. The project was supported by the Agence Nationale pour la Recherche grant ANR-06-PHISIO-004-01, ANR-2010-BLAN-1128-01, ANR-09-GENO-034 and ANR-13-BSV1-0023-02, the NIH R01HL087120-A2 grant (M.M.), the NIH R01HL105550 (K.W.), the Fondation de France grant 2008002730 (J.N.), the Fondation pour la Recherche Medicale grant DPC20111122986 (A.F.), the Deutsche For-schungsgemeinschaft grant IS63/1–1/2 (D.I. and H.E), IS63/3-1/2 (D.I.), and DFG FOR 604 and Es 88/10-1 (T.E.). P.M. was supported by the CavNet, a Research Training Network (RTN) funded through the European Union Research Programme (6FP) MRTN-CT-2006-035367. L.M. is a recipient of a postdoctoral fellowship by the Fondation Lefoulon-Delalande. We also thank the Montpellier RIO Imaging facility and their financing bodies. The IGF group is a member of the Laboratory of Excellence ) Ion Channel Science and Therapeutics * supported by a grant from ANR (ANR-11-LABX-0015).

PY - 2014/8/21

Y1 - 2014/8/21

N2 - The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (I f) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific I f silencing caused altered [Ca2+] i release and Ca 2+ handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of I f silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in I f-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

AB - The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (I f) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific I f silencing caused altered [Ca2+] i release and Ca 2+ handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of I f silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in I f-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

UR - http://www.scopus.com/inward/record.url?scp=84907313546&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907313546&partnerID=8YFLogxK

U2 - 10.1038/ncomms5664

DO - 10.1038/ncomms5664

M3 - Article

C2 - 25144323

AN - SCOPUS:84907313546

SN - 2041-1723

VL - 5

JO - Nature communications

JF - Nature communications

M1 - 4664

ER -

Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation

Abstract

Bibliographical note

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this