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Ion Channels As Part of Macromolecular Multiprotein Complexes Clinical Significance

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Ion Channels As Part of Macromolecular Multiprotein Complexes Clinical Significance Schwerpunkt Herzschr Elektrophys 2018 · 29:30–35 Jordi Heijman1 · Dobromir Dobrev2 https://doi.org/10.1007/s00399-017-0542-y 1 Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Received: 9 August 2017 Life Sciences, Maastricht University, Maastricht, The Netherlands Accepted: 11 October 2017 2 Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Published online: 6 December 2017 Duisburg-Essen, Essen, Germany © The Author(s) 2017. This article is an open access publication. Ion channels as part of macromolecular multiprotein complexes Clinical significance Introduction Cardiac cellular electrophysiol- Na+ and K+ concentrations is achieved ogy and arrhythmogenesis via the Na+-K+-ATPase. Every heartbeat is orchestrated by a cas- Each of these ion channels is in fact cade of electrical activity that initiates Although there are important quantita- a large macromolecular complex consist- contraction in cardiomyocytes through tive differences in cellular electrophys- ingofnumerousproteinsthatregulate a process termed excitation–contraction iology and Ca2+ handling between dif- the intracellular movement and distri- coupling [1, 2]. The electrophysiological ferent cardiac regions (reviewed in [1, bution (a processes termed trafficking) properties of cardiomyocytes are dy- 2, 4]), a number of commonalities and and function of these channels. Dys- namically regulated to adapt to varying general mechanisms can be highlighted. function of any of these ion channels demands. Research performed during The upstroke of the action potential (AP) in the setting of cardiovascular disease the past 20 years has shown that the ion in cardiomyocytes is mediated by Na+ may predispose to atrial or ventricular channelsand Ca2+-handlingproteinsthat influx through voltage-dependent Na+ arrhythmias by promoting triggered ac- are essential for cardiomyocyte electro- channels. The resulting depolarization tivity or reentry; the major conceptual physiology and excitation–contraction of the membrane potential subsequently arrhythmogenic mechanisms (. Fig. 1b; coupling are organized in large macro- activatesseveralothervoltage-dependent [2, 5]). In particular, loss of function of molecular multiprotein complexes [3]. ion channels. Activation of L-type Ca2+ repolarizing currents may produce ex- In these macromolecular complexes, channels produces a depolarizing inward cessive AP prolongation, giving rise to numerous proteins interact to form current that shapes the plateau phase of early afterdepolarizations that may lead a functional unit, such as an ion chan- the AP, whereas a range of K+ channels to triggered activity. Triggered activity nel. Moreover, the precise composition with different kinetic properties (e. g., is also promoted by Ca2+-handling ab- of the macromolecular complexes in slow, rapid or ultrarapid activation) con- normalities activating NCX1, resulting the cell membrane critically controls trol repolarization [2]. Finally, the rest- in transient inward currents and delayed the dynamic regulation of ion channel ing membrane potential is largely de- afterdepolarizations. On the other hand, function. As such, alterations in the termined by inward-rectifier and back- shortening of repolarization (e. g., due to composition of these macromolecular ground K+ currents (. Fig. 1a). an increase in K+ currents) or slowing of complexes can promote ion channel The influx of Ca2+ into the cardiomy- conduction velocity (e. g., due to loss of 2+ + dysfunction with subsequent arrhyth- ocyte through L-type Ca channels also Na current [INa]orimpairedintercellu- mias in various cardiovascular diseases. triggers a much larger Ca2+ release from lar communication) increases the likeli- After a brief introduction of cardiac the intracellular stores of the sarcoplas- hood of reentrant arrhythmias. Studies cellular electrophysiology, we describe mic reticulum (SR) through type 2 ryan- in animal models and human samples the major general components of ion odine receptor (RyR2) channels, giving performed over the last 20 years have channel macromolecular complexes in rise to the systolic Ca2+ transientthatac- provided important information about the heart. Finally, we highlight the po- tivates the contractile machinery [1]. Re- the role of different ion channel macro- tential clinical relevance of alterations laxation occurs when Ca2+ is taken back molecular complexes in these fundamen- in the qualitative and quantitative com- up into the SR via the SR Ca2+-ATPase tal mechanisms of cardiac arrhythmoge- position of macromolecular ion channel type 2a (SERCA2a) and transported out nesis [5]. complexes. of the cell via the Na+/Ca2+ exchanger type 1 (NCX1). Finally, homeostasis of 30 Herzschrittmachertherapie + Elektrophysiologie 1 · 2018 Cardiac action potential Ion-channel macromolecular complexes I to I Genetic Impaired subunit Ca, L mutations expression Regulation of subcellular trafficking, localization and function I ,I of ion channels and Ca2+-handling proteins Kr Ks Ectopic Activity Reentry I Na (early/delayed (short ERP, slow I ,I after depolarizations) conduction) NaK NCX I K1 Cardiac arrhythmias ab Fig. 1 8 Theroleofionchannelmacromolecularcomplexesincardiacelectrophysiologyandarrhythmogenesis.aSchematic + representationofthecardiacactionpotentialandthemajorunderlyingioncurrents. INa fastNa current,Ito transient-outward + 2+ + + + + K current, ICa,L L-type Ca current, IKr rapid delayed-rectifier K current, IKs slow delayed-rectifier K current, INaK Na -K - + 2+ + ATPase current, INCX Na /Ca exchanger current; IK1 basal inward-rectifier K current. b Macromolecular complexes ensure proper trafficking, localization and function of ion channels, thereby preventing occurrence of ectopic activity and reentry, the primary mechanisms of cardiac arrhythmias.This regulation may be disturbed by genetic mutations or impaired expres- sion of individual components of the macromolecular complex.ERP effective refractory period Fig. 2 8 Regulation of ion channels and sarcoplasmic reticulum (SR) Ca2+-handling proteins through macromolecular com- plexes. a The composition of the macromolecular complex controls:1 Trafficking, localization and mechanosensitive reg- ulation of ion channels and Ca2+-handling proteins, e. g., through regulatory subunits (cyan ellipses) that mask endoplasmic reticulumretentionsignalsorproteinsinteractingwithvariouscomponentsofthecytoskeleton(red);2Posttranslationalmod- ifications,e. g.,phosphorylation(orange “P”)throughanchoringofproteinkinases(PK),phosphatases(PP)andotherenzymes (green);3Ca2+-dependentregulation,e. g.,mediatedbycalmodulin(purple);and4Channelgatingandbiophysicalproperties, e. g.,throughregulatorysubunits. bExampleofthemacromolecularcomplexcontrollingtheslowdelayed-rectifierK+current (IKs). The channel consists of a tetramer of Kv7.1 pore-forming α subunits, KCNE1 β subunits, an A-kinase anchoring protein (Yotiao) that targets protein kinase A (PKA), protein phosphatase type-1 (PP1), adenylyl cyclase (AC), and phosphodiesterase (PDE) 4D3 to the channel, as well as the Ca2+-binding protein calmodulin (CaM), protein kinase C (PKC), phosphatidylinositol 4,5-bisphosphate (PIP2)andβ-tubulin Common components of review articles [3, 6–8]. Here, we provide Regulatory subunits macromolecular complexes a more general overview of the different types of proteins and their roles in ion Inmostionchannels, oneprotein(e. g., in A detailed description of the composition channel (dys)function. These roles are the case of Na+ channels and L-type Ca2+ of individual macromolecular complexes also summarized in . Fig. 2a. channels) or a multimer of one or more of ion channels and Ca2+ transport mech- proteins (e. g., a homotetramer of Kv7.1 anisms has been given in a number of proteins in the slow delayed-rectifier K+ Herzschrittmachertherapie + Elektrophysiologie 1 · 2018 31 Abstract · Zusammenfassung channel) form the primary pore-forming Herzschr Elektrophys 2018 · 29:30–35 https://doi.org/10.1007/s00399-017-0542-y α subunit through which ions cross the © The Author(s) 2017. This article is an open access publication. cell membrane. In most cases, the pore- forming α subunit interacts with several J. Heijman · D. Dobrev regulatory subunits that further regulate Ion channels as part of macromolecular multiprotein complexes. ion channel function. For example, inter- Clinical significance action between the pore-forming Kv7.1 subunit and KCNE1 β subunits is re- Abstract quired to produce the characteristic slow Ion channels and Ca2+-handling proteins in the expression of individual components, may lead to ion channel dysfunction and activation kinetics of the slow delayed- involved in the regulation of cardiac electro- arrhythmogenesis. Here, we review novel + physiology and contractility are organized rectifier K current (IKs)thatcontributes in macromolecular multiprotein complexes. insights into the composition of the major to repolarization of the AP (. Fig. 2b; Recent molecular and cellular studies have ion channel macromolecular complexes and [9]). Most other ion channels similarly significantly enhanced our understanding of discuss the potential clinical significance of associate with different β subunits [3, the composition of these macromolecular alterations in these dynamic multiprotein structures. 7]. Interestingly, however, the exact stoi- complexes and have helped to elucidate their role in the dynamic regulation of ion channel chiometry between pore-forming α sub-
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