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          Institute: MPI für medizinische Forschung     Collection: Jahrbuch 2012     Display Documents

ID: 638134.0, MPI für medizinische Forschung / Jahrbuch 2012
Altered HCN4 channel C−linker interaction is associated with familial tachycardia−bradycardia syndrome and atrial fibrillation
Translation of Title:Altered HCN4 channel C−linker interaction is associated with familial tachycardia−bradycardia syndrome and atrial fibrillation
Authors:Duhme, Nana; Schweizer, Patrick A.; Thomas, Dierk; Becker, Rüdiger; Schröter, Julian; Barends, Thomas; Schlichting, Ilme; Draguhn, Andreas; Bruehl, Claus; Katus, Hugo A.; Koenen, Michael
Date of Publication (YYYY-MM-DD):2012-11-23
Title of Journal:European Heart Journal
Journal Abbrev.:European Heart Journal
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Aims HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to the generation of cardiac tachyarrhythmias.

Methods and results In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4−K530N) in a highly conserved region of the C−linker. The index patient developed tachycardia−bradycardia syndrome and persistent atrial fibrillation (AF) in an age−dependent fashion. Pedigree analysis identified eight affected family members with a similar course of disease. Whole−cell patch clamp electrophysiology of HEK293 cells showed that homomeric mutant channels almost are indistinguishable from wild−type channels. In contrast, heteromeric channels composed of mutant and wild−type subunits displayed a significant hyperpolarizing shift in the half−maximal activation voltage. This may be caused by a shift in the equilibrium between the tonically inhibited nucleotide−free state of the C−terminal domain of HCN4 believed to consist of a ‘dimer of dimers' and the activated ligand−bound tetrameric form, leading to an increased inhibition of activity in heteromeric channels.

Conclusion Altered C−linker oligomerization in heteromeric channels is considered to promote familial tachycardia−bradycardia syndrome and persistent AF, indicating that f−channel dysfunction contributes to the development of atrial tachyarrhythmias
Free Keywords:Sinoatrial node
Atrial fibrillation
Ion channels
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Abteilung Biophysik
MPI für medizinische Forschung/Abteilung Zellphysiologie
MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen
MPI für medizinische Forschung/Abteilung Zellphysiologie/Molekulare Anatomie neuromuskulärer Synapsen
MPI für medizinische Forschung/Arbeitsgruppe Witzemann / Koenen
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen/Molecular chaperones
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen/Heme and Flavin Enzymes
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen/Coherent diffractive imaging
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