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.
Bibliographical noteFunding 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).