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Structure and function of cardiac potassium channels

Structure and function of cardiac potassium channels AbstractRecent advances in molecular biology have had a major impact on our understanding of the biophysical and molecular properties of ion channels. This review is focused on cardiac potassium channels which, in general, serve to control and limit cardiac excitability. Approximately 60 K+ channel subunits have been cloned to date. The (evolutionary) oldest potassium channel subunits consist of two transmembrane (Tm) segments with an intervening pore-loop (P). Channels formed by four 2Tm–1P subunits generally function as inwardly rectifying K+-selective channels (KirX.Y): they conduct substantial current near the resting potential but carry little or no current at depolarized potentials. The inward rectifier IK1 and the ligand-gated KATP and KACh channels are composed of such subunits. The second major class of K+ channel subunits consists of six transmembrane segments (S1–S6). The S5–P–S6 section resembles the 2Tm–1P subunit, and the additional membrane-spanning segments (especially the charged S4 segment) endow these 6Tm–1P channels with voltage-dependent gating. For both major families, four subunits assemble into a homo- or heterotetrameric channel, subject to specific subunit–subunit interactions. The 6Tm–1P channels are closed at the resting potential, but activate at different rates upon depolarization to carry sustained or transient outward currents (the latter due to inactivation by different mechanisms). Cardiac cells typically display at least one transient outward current and several delayed rectifiers to control the duration of the action potential. The molecular basis for each of these currents is formed by subunits that belong to different Kvx.y subfamilies and alternative splicing can contribute further to the diversity in native cells. These subunits display distinct pharmacological properties and drug-binding sites have been identified. Additional subunits have evolved by concatenation of two 2Tm–1P subunits (4Tm–2P); dimers of such subunits yield voltage-independent leak channels. A special class of 6Tm–1P subunits encodes the ‘funny’ pacemaker current which activates upon hyperpolarization and carries both Na+ and K+ ions. The regional heterogeneity of K+ currents and action potential duration is explained by the heterogeneity of subunit expression, and significant changes in expression occur in cardiac disease, most frequently a reduction. This electrical remodelling may also be important for novel antiarrhythmic therapeutic strategies. The recent crystallization of a 2Tm–1P channel enhances the outlook for more refined molecular approaches. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiovascular Research Oxford University Press

Structure and function of cardiac potassium channels

Snyders, Dirk J
Cardiovascular Research , Volume 42 (2) – May 1, 1999
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References (157)

Publisher
Oxford University Press
Copyright
Copyright © 1999, European Society of Cardiology
ISSN
0008-6363
eISSN
1755-3245
DOI
10.1016/S0008-6363(99)00071-1
Publisher site
See Article on Publisher Site

Abstract

AbstractRecent advances in molecular biology have had a major impact on our understanding of the biophysical and molecular properties of ion channels. This review is focused on cardiac potassium channels which, in general, serve to control and limit cardiac excitability. Approximately 60 K+ channel subunits have been cloned to date. The (evolutionary) oldest potassium channel subunits consist of two transmembrane (Tm) segments with an intervening pore-loop (P). Channels formed by four 2Tm–1P subunits generally function as inwardly rectifying K+-selective channels (KirX.Y): they conduct substantial current near the resting potential but carry little or no current at depolarized potentials. The inward rectifier IK1 and the ligand-gated KATP and KACh channels are composed of such subunits. The second major class of K+ channel subunits consists of six transmembrane segments (S1–S6). The S5–P–S6 section resembles the 2Tm–1P subunit, and the additional membrane-spanning segments (especially the charged S4 segment) endow these 6Tm–1P channels with voltage-dependent gating. For both major families, four subunits assemble into a homo- or heterotetrameric channel, subject to specific subunit–subunit interactions. The 6Tm–1P channels are closed at the resting potential, but activate at different rates upon depolarization to carry sustained or transient outward currents (the latter due to inactivation by different mechanisms). Cardiac cells typically display at least one transient outward current and several delayed rectifiers to control the duration of the action potential. The molecular basis for each of these currents is formed by subunits that belong to different Kvx.y subfamilies and alternative splicing can contribute further to the diversity in native cells. These subunits display distinct pharmacological properties and drug-binding sites have been identified. Additional subunits have evolved by concatenation of two 2Tm–1P subunits (4Tm–2P); dimers of such subunits yield voltage-independent leak channels. A special class of 6Tm–1P subunits encodes the ‘funny’ pacemaker current which activates upon hyperpolarization and carries both Na+ and K+ ions. The regional heterogeneity of K+ currents and action potential duration is explained by the heterogeneity of subunit expression, and significant changes in expression occur in cardiac disease, most frequently a reduction. This electrical remodelling may also be important for novel antiarrhythmic therapeutic strategies. The recent crystallization of a 2Tm–1P channel enhances the outlook for more refined molecular approaches.

Journal

Cardiovascular Research – Oxford University Press

Published: May 1, 1999

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