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Vol. 30, No. 5, 2012
Issue release date: November 2012
Section title: Original Paper
Cell Physiol Biochem 2012;30:1227-1240
(DOI:10.1159/000343314)

The HCN4 Channel Mutation D553N Associated With Bradycardia Has a C-linker Mediated Gating Defect

Netter M.F. · Zuzarte M. · Schlichthörl G. · Klöcker N. · Decher N.
a Institute of Physiology and Pathophysiology, Vegetative Physiology Group, Philipps University of Marburg; b Institute of Physiology and Pathophysiology, Cardiovascular Cellphysiology Group, Philipps University of Marburg; c Institute of Neuro- and Sensory Physiology, Medical Faculty, University of Düsseldorf

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Abstract

Background/Aims: The D553N mutation located in the C-linker of the cardiac pacemaker channel HCN4 is thought to cause sino-atrial dysfunction via a pronounced dominant-negative trafficking defect. Since HCN4 mutations usually have a minor defect in channel gating, it was our aim to further characterize the disease causing mechanism of D553N. Methods: Fluorescence microscopy, FACS, TEVC and patch-clamp recordings were performed to characterize D553N. Results: Surprisingly, we found that D553N channels reach the plasma membrane and have no apparent trafficking defect. Co-expression of D553N with HCN4 also revealed no dominant-negative effect on wild-type channels. Consistent with the normal cell surface expression of D553N, it was possible to extensively characterize D553N mutants in Xenopus oocytes and mammalian cells. D553N channels generate currents with reduced amplitude, while the kinetics of activation and deactivation are not altered. While the regulation of D553N by tyrosine kinases is normal, we observed a change in the cAMP regulation which however cannot account for the strong loss-of-function of the mutant. Conclusion: The pronounced current reduction and the regular surface expression indicate a major gating defect of the C-linker gate. We hypothesize that the D553N mutation stabilizes a previously reported salt bridge important for the gating of the channel.


  

Author Contacts

Niels Decher
Institut für Physiologie, Vegetative Physiologie,
Universität Marburg, Deutschhausstraße 1-2, 35037 Marburg (Germany)
Tel. +49 6421 28 62148, Fax +49 6421 28 66659, E-Mail decher@staff.uni-marburg.de

  

Article Information

Accepted: August 24, 2012
Published online: October 15, 2012
Number of Print Pages : 14

  

Publication Details

Cellular Physiology and Biochemistry (International Journal of Experimental Cellular Physiology, Biochemistry and Pharmacology)

Vol. 30, No. 5, Year 2012 (Cover Date: November 2012)

Journal Editor: Guggino W. (Baltimore, Md.), Lang F. (Tübingen)
ISSN: 1015-8987 (Print), eISSN: 1421-9778 (Online)

For additional information: http://www.karger.com/CPB


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: 8/24/2012
Published online: 10/15/2012

Number of Print Pages: 14
Number of Figures: 2
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: http://www.karger.com/CPB


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