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FASEB J. 2018 Nov;32(11):6159-6173. doi: 10.1096/fj.201800246R. Epub 2018 Jun 7.

The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function.

Author information

1
Institute of Physiology and Pathophysiology, Vegetative Physiology, Phillips University, Marburg, Germany.
2
Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany.
3
Molecular Cardiology, Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany.
4
Institute for Physiology I, University of Münster, Munster, Germany.
5
Department of Cardiology II - Electrophysiology, University Hospital Münster, University of Münster, Munster, Germany.
6
Institute of Physiology, Christian-Albrechts University, Kiel, Germany.
7
Institute of Pharmacology and Clinical Pharmacy, Phillips University, Marburg, Germany.
8
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
9
Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
10
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
11
INSERM, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
12
Institute of Cardiovascular Sciences, University Hospital Birmingham, University of Birmingham, Birmingham, United Kingdom.
13
Department of Cardiology, University Hospital Birmingham, University of Birmingham, Birmingham, United Kingdom.
14
Division of Rhythmology, Department of Genetic Epidemiology, University Hospital Münster, University of Münster, Munster, Germany.
15
Institute of Human Genetics, Department of Genetic Epidemiology, University Hospital Münster, University of Münster, Munster, Germany.

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels encode neuronal and cardiac pacemaker currents. The composition of pacemaker channel complexes in different tissues is poorly understood, and the presence of additional HCN modulating subunits was speculated. Here we show that vesicle-associated membrane protein-associated protein B (VAPB), previously associated with a familial form of amyotrophic lateral sclerosis 8, is an essential HCN1 and HCN2 modulator. VAPB significantly increases HCN2 currents and surface expression and has a major influence on the dendritic neuronal distribution of HCN2. Severe cardiac bradycardias in VAPB-deficient zebrafish and VAPB-/- mice highlight that VAPB physiologically serves to increase cardiac pacemaker currents. An altered T-wave morphology observed in the ECGs of VAPB-/- mice supports the recently proposed role of HCN channels for ventricular repolarization. The critical function of VAPB in native pacemaker channel complexes will be relevant for our understanding of cardiac arrhythmias and epilepsies, and provides an unexpected link between these diseases and amyotrophic lateral sclerosis.-Silbernagel, N., Walecki, M., Schäfer, M.-K. H., Kessler, M., Zobeiri, M., Rinné, S., Kiper, A. K., Komadowski, M. A., Vowinkel, K. S., Wemhöner, K., Fortmüller, L., Schewe, M., Dolga, A. M., Scekic-Zahirovic, J., Matschke, L. A., Culmsee, C., Baukrowitz, T., Monassier, L., Ullrich, N. D., Dupuis, L., Just, S., Budde, T., Fabritz, L., Decher, N. The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function.

KEYWORDS:

ALS; HCN channels; cardiac arrhythmia

PMID:
29879376
PMCID:
PMC6629115
DOI:
10.1096/fj.201800246R
[Indexed for MEDLINE]
Free PMC Article

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