Mesirca, Pietro ORCID: 0000-0002-9538-3096, Alig, Jacqueline, Torrente, Angelo G., Mueller, Jana Christina, Marger, Laurine, Rollin, Anne, Marquilly, Claire, Vincent, Anne ORCID: 0000-0002-4743-2068, Dubel, Stefan, Bidaud, Isabelle, Fernandez, Anne, Seniuk, Anika, Engeland, Birgit, Singh, Jasmin, Miquerol, Lucile, Ehmke, Heimo, Eschenhagen, Thomas, Nargeot, Joel ORCID: 0000-0003-2893-5636, Wickman, Kevin ORCID: 0000-0002-5179-9540, Isbrandt, Dirk and Mangoni, Matteo E. (2014). Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nat. Commun., 5. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

Full text not available from this repository.

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 (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific I-f silencing caused altered [Ca2+](i) release and Ca2+ 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mesirca, PietroUNSPECIFIEDorcid.org/0000-0002-9538-3096UNSPECIFIED
Alig, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torrente, Angelo G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Jana ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marger, LaurineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rollin, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marquilly, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vincent, AnneUNSPECIFIEDorcid.org/0000-0002-4743-2068UNSPECIFIED
Dubel, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bidaud, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seniuk, AnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engeland, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singh, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miquerol, LucileUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehmke, HeimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eschenhagen, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nargeot, JoelUNSPECIFIEDorcid.org/0000-0003-2893-5636UNSPECIFIED
Wickman, KevinUNSPECIFIEDorcid.org/0000-0002-5179-9540UNSPECIFIED
Isbrandt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangoni, Matteo E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-432567
DOI: 10.1038/ncomms5664
Journal or Publication Title: Nat. Commun.
Volume: 5
Date: 2014
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RABBIT SINOATRIAL NODE; SICK SINUS SYNDROME; PACEMAKER ACTIVITY; HEART-RATE; HCN CHANNELS; K+ CHANNEL; MOLECULAR CHARACTERIZATION; CAMP SENSITIVITY; IONIC CURRENTS; CA2+ RELEASEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43256

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item