Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition

Author:

Xiao Ling1,Koopmann Tamara T.1,Ördög Balázs1,Postema Pieter G.1,Verkerk Arie O.1,Iyer Vivek1,Sampson Kevin J.1,Boink Gerard J.J.1,Mamarbachi Maya A.1,Varro Andras1,Jordaens Luc1,Res Jan1,Kass Robert S.1,Wilde Arthur A.1,Bezzina C.R.1,Nattel Stanley1

Affiliation:

1. From the Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada (L.X., B.O., M.A.M., S.N.); Department of Clinical and Experimental Cardiology (T.T.K., P.G.P., G.J., J.B., A.A.W., C.R.B.) and Department of Anatomy, Embryology and Physiology (A.O.V.), Heart Failure Research Center, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (V.I., K.J.S., R.S.K.);...

Abstract

Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I to had similar density, but PF I to differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

Reference53 articles.

1. Sudden Cardiac Death Prediction and Prevention

2. Survivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition and standardized clinical evaluation: Consensus Statement of the Joint Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry in the United States.;Circulation,1996

3. Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation

4. Weighing the evidence for a ternary protein complex mediating A-type K+currents in neurons

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3