Protein assemblies of sodium and inward rectifier potassium channels control cardiac excitability and arrhythmogenesis

American Journal of Physiology - Heart and Circulatory Physiology - Tập 308 Số 12 - Trang H1463-H1473 - 2015
B. Cicero Willis1, Daniela Ponce‐Balbuena1, José Jalife2,3
1Department of Internal Medicine and Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan; and
21Department of Internal Medicine and Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan; and
32Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain

Tóm tắt

The understanding of how cardiac ion channels function in the normal and the diseased heart has greatly increased over the last four decades thanks to the advent of patch-clamp technology and, more recently, the emergence of genetics, as well as cellular and molecular cardiology. However, our knowledge of how these membrane-embedded proteins physically interact with each other within macromolecular complexes remains incomplete. This review focuses on how the main cardiac inward sodium channel (NaV1.5) and the strong inward rectifier potassium channel (Kir2.1) function within macromolecular complexes to control cardiac excitability. It has become increasingly clear that these two important ion channel proteins physically interact with multiple other protein partners and with each other from early stages of protein trafficking and targeting through membrane anchoring, recycling, and degradation. Recent findings include compartmentalized regulation of NaV1.5 channel expression and function through a PDZ (postsynaptic density protein, Drosophila disc large tumor suppressor, and zonula occludens-1 protein) domain-binding motif, and interaction of caveolin-3 with Kir2.1 and ankyrin-G as a molecular platform for NaV1.5 signaling. At the cardiomyocyte membrane, NaV1.5 and Kir2.1 interact through at least two distinct PDZ domain-scaffolding proteins (synapse-associated protein-97 and α1-syntrophin), thus modulating reciprocally their cell-surface expression at two different microdomains. Emerging evidence also shows that inheritable mutations in plakophilin-2, ankyrin-G, dystrophin, syntrophin, synapse-associated protein-97, and caveolin-3, among others, modify functional expression and/or localization in the cardiac cell of NaV1.5, Kir2.1 or both to give rise to arrhythmogenic diseases. Unveiling the mechanistic underpinnings of macromolecular interactions should increase our understanding of inherited and acquired arrhythmogenic cardiac diseases and may lead to advances in therapy.

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Tài liệu tham khảo

10.1016/j.yjmcc.2009.08.025

10.1016/j.cardiores.2007.07.019

10.1007/978-3-642-41588-3_7

10.1126/scitranslmed.3008008

10.1016/j.pbiomolbio.2009.01.012

10.1152/physrev.00041.2011

10.1161/hh0102.102977

10.1161/hh1201.093270

10.1074/jbc.M310278200

10.1038/415198a

10.1016/0735-1097(92)90253-J

10.1126/science.6320365

10.1146/annurev.bi.55.070186.004513

10.1161/CIRCULATIONAHA.113.003077

10.1093/cvr/cvs218

10.1038/32675

10.1093/cvr/cvs211

10.1152/physrev.00046.2003

10.1016/j.hrthm.2006.11.030

10.1016/j.cardiores.2006.03.018

10.1161/01.RES.0000128408.66946.67

10.1212/01.WNL.0000072261.14060.47

10.1080/17431380410032490

Ehmsen J, 2002, J Cell Sci, 115, 2801, 10.1242/jcs.115.14.2801

10.1161/CIRCRESAHA.108.191007

10.1038/nrm1052

10.1161/01.RES.0000237466.13252.5e

10.1038/ng1461

10.1016/j.hrthm.2014.09.057

10.1016/S0008-6363(02)00602-8

10.1016/S0896-6273(00)00116-1

10.1016/j.hrthm.2013.09.064

10.1172/JCI43621

10.1016/B978-1-4557-2856-5.00021-2

10.1161/CIRCGENETICS.110.959130

10.1038/378085a0

10.1124/pr.57.4.11

10.1074/jbc.M303327200

10.1074/jbc.M400285200

10.1074/jbc.M400284200

Leonoudakis D, 2001, J Cell Sci, 114, 987, 10.1242/jcs.114.5.987

10.1074/jbc.M207074200

10.1161/CIRCULATIONAHA.107.703330

10.1083/jcb.200710107

10.1016/j.cell.2011.06.007

10.1161/CIRCRESAHA.115.305154

10.1152/ajpheart.00934.2001

10.1073/pnas.1109370109

10.1161/CIRCULATIONAHA.106.656512

10.1073/pnas.0403711101

10.1038/nature01335

10.1085/jgp.200308929

10.1161/01.RES.78.1.1

10.1161/CIRCRESAHA.110.228312

10.1016/S0092-8674(01)00342-7

10.1161/01.RES.0000162101.76263.8c

10.1073/pnas.1323541111

10.1074/jbc.M104471200

10.1093/cvr/cvs219

10.1146/annurev.physiol.64.083101.145105

10.1073/pnas.86.20.8170

10.1523/JNEUROSCI.3515-07.2007

10.1074/jbc.M307479200

10.1161/CIRCRESAHA.111.247023

10.1161/CIRCRESAHA.109.201418

10.1002/humu.9144

10.1111/jcmm.12335

10.1111/j.1540-8167.2006.00387.x

10.1113/jphysiol.1992.sp019066

10.1161/CIRCULATIONAHA.113.007852

10.1016/S0735-1097(02)01962-9

10.1016/j.hrthm.2010.01.032

10.1172/JCI15183

10.1073/pnas.0801294105

10.1074/jbc.M110.110858

10.1074/jbc.M112.435370

10.1016/j.cardiores.2004.01.022

10.1152/ajpheart.00513.2009

10.1161/CIRCULATIONAHA.107.704627

10.1016/j.hrthm.2008.02.034

10.1161/CIRCULATIONAHA.106.635268

10.1152/ajpheart.00638.2008

10.1161/CIRCRESAHA.111.247957

10.1016/0092-8674(95)90359-3

10.1161/01.CIR.98.22.2422

10.1161/CIRCEP.108.769224

10.1074/jbc.M709721200

10.1161/hh0402.105177

10.1016/j.tcb.2009.12.001

10.1016/j.tcm.2007.08.001

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American Journal of Physiology - Heart and Circulatory Physiology

Tập 308 Số 12

H1463-H1473

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