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

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 expression 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 complexes. a The composition of the macromolecular complex controls:1 Trafficking, localization and mechanosensitive regulation 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- function. Moreover, it has become clear that Keywords units and regulatory β subunits remains alterations in the composition of ion channel Cardiac arrhythmias · Calcium · Electro- a topic of debate for most ion channels macromolecular complexes, for example, due physiology · Macromolecular complex · [3, 8]. Besides classical transmembrane to genetic mutations or acquired alterations Phosphorylation β subunits such as KCNE1, a wide range of other interacting proteins, binding to otherparts ofthe pore-forming α subunit, Ionenkanäle als Teil makromolekularer Multiproteinkomplexe. regulate the function of ion channels and Klinische Signifikanz 2+ Ca -handling proteins. For example, at Zusammenfassung least a dozen regulatory subunits have Die physiologische Funktion von Ionenkanä- Arrhythmien führen können. In diesem beenidentifiedaspartoftheRyR2macro- len erfordert eine präzise Regulation, die Übersichtsartikel fassen wir die Regulation molecular complex [1, 10], including FK- zum Teil über die Bildung makromolekularer der makromolekularen Multiproteinkomplexe 506 binding protein 12.6 (FKBP12.6), Multiproteinkomplexe gewährleistet wird. ausgewählter Ionenkanäle zusammen und Studien auf zellulärer und molekularer diskutieren die möglichen klinischen Folgen which enhances cooperation between the Ebene konnten unser Verständnis über die von Veränderungen in der Funktion oder four pore-forming α subunits, regulating dynamischen Regulationsmechanismen der Zusammensetzung dieser dynamischen the stability of the channel’s closed state. Ionenkanalkomplexe deutlich verbessern. Multiproteinstrukturen. In addition, FKBP12.6 plays a role in Es ist inzwischen etabliert, dass genetische coupled-gating between different RyR2 Mutationen oder erworbene Störungen in Schlüsselwörter der Expression oder Funktion der beteiligten Herzrhythmusstörungen · Kalzium · Elektro- channels. This process, whereby two Komplexpartner zu Ionenkanaldysfunktionen physiologie · Makromolekularer Komplex · or more connected RyR2 channels can und zum Auftreten von lebensbedrohlichen Phosphorylierung gate simultaneously, is critical for the rapid synchronous initiation of SR Ca2+ release and excitation–contraction coupling [10]. signals present in their α subunits that where exactly these ion channels traffic. normally ensure that these subunits get Interactions with different components Components involved in retained in subcellular compartments of the actin or microtubule cytoskeleton trafficking, subcellular localization, (so-called endoplasmic reticulum re- appear to play a critical role in this tar- and degradation tention signals). Thus, the interaction geting [14]. For example, the last three with regulatory subunits increases the residues of the Na+ channel α subunit The number of ion channels on the mem- number of functional channels in the form a PDZ-binding motif that enables brane of a cardiomyocyte that determine plasma membrane [12]. In agreement interaction with syntrophin and SAP97 the cardiac AP is dynamically regulated with this important role in trafficking, proteins, which is required for expres- via trafficking, degradation, and recy- transmural differences in the expression of the Na+ channel macromolecular cling pathways [11, 12]. For several ion sion of the KChIP2 regulatory protein complex at the lateral membrane, but channels it has been established that determine the gradient in transient- notattheintercalateddisk[15]. Correct + the composition of the macromolecu- outward K current Ito from epicardial targeting of individual macromolecular lar complex plays a major role in their to endocardial layers of the heart [8, complexes is necessary for their correct + trafficking. For example, for IKs,Na 13]. Interestingly, recent evidence has functioning. For example, plasma mem- 2+ 2+ and L-type Ca channels the interaction indicated that the composition of the brane targeting of Ca channel Cav1.3 with regulatory subunits strongly pro- macromolecular complex not only fa- α subunits requires direct interaction motes forward trafficking by masking cilitates trafficking, but also determines with the multifunctional adapter protein

32 Herzschrittmachertherapie + Elektrophysiologie 1 · 2018 ankyrin-B to ensure proper Ca2+ channel phosphatases, it has been shown that Ca2+-dependent small-conductance K+ 2+ function [16]. Also, the Ca -induced AKAPs also recruit other components channels (SK channels) and IKs chan- Ca2+ release from the SR requires a close of the β-adrenoceptor signaling cascade nels, which enable a close bidirectional interaction between RyR2 and L-type to the vicinity of ion channels and Ca2+- coupling between cellular electrophys- Ca2+ channels [1]. This interaction de- handling proteins. For example, both iology and Ca2+ handling [3, 8, 25]. pends in part on junctophilin 2 proteins Yotiao and mAKAP also bind adenylyl Besides calmodulin, other Ca2+-binding that interact with RyR2 and the T-tubular cyclases responsible for cAMP produc- proteins can regulate the function of dif- membranewhereL-typeCa2+ channels tion and phosphodiesterases responsible ferent macromolecular complexes. For are predominantly located. Likewise, βII for cAMP degradation, thereby expand- example, calsequestrin 2 is a Ca2+ buffer spectrin, an actin-associated molecule, ing the fine tuning of local regulation of located in the SR that also modulates is also required for proper RyR2 channel ion channel function [21, 22]. It is likely gating of RyR2 channels in response to targeting [17]. Thus, the presence of that the composition of the macro- changes in SR Ca2+ concentrations [1]. junctophilin 2 and βII spectrin in the molecular complex similarly controls Similarly, SR Ca2+ uptake via SERCA2a is RyR2 macromolecular complex is critical other posttranslational modifications. negatively regulated by phospholamban for normal excitation–contraction cou- Indeed, caveolin-3 and syntrophin have and the interaction between SERCA2a pling. Finally, interacting proteins may been suggested to regulate Na+ chan- and phospholamban is Ca2+ dependent also determine the stability and degra- nel S-nitrosylation [7]andrecentdata [27], providing a way to improve SR dation of ion channels, as has recently have identified sirtuin 1 deacetylase as Ca2+ uptake under conditions of high been shown for the L-type Ca2+ channel part of the Na+ channel macromolec- cytosolic Ca2+. and its interacting protein polycystin 1 ular complex controlling acetylation- Cardiac electrophysiology is also reg- [18]. mediated changes in INa [24]. However, ulatedbymechanicalforcesactingoncar- in general the molecular mechanisms diomyocytes through a process termed Components involved in ion controlling these other posttranslational mechano-electric feedback [28]. In addi- channel posttranslational modifications are less well established in tiontomechanicallygated channels(e. g., modifications the heart. stretch-activatedchannels), severaltradi- tionalvoltage-gated ionchannels, includ- After trafficking to their specific subcel- Ca2+-dependent and mechanical ing Na+ channels and inward-rectifier K+ lular location, almost all ion channels regulation of ion channels currents, are nowknowntobe modulated undergo various posttranslational mod- by mechanical forces [28]. For most volt- ifications that dynamically regulate their Given the central role of Ca2+ in the age-gated ion channels the interaction biophysical properties [19]. Among short- and long-term regulation of car- with the lipid bilayer and cytoskeleton these posttranslational modifications, diac function, it is not surprising that plays an essential role in their mechanical phosphorylation by serine/threonine a large number of feedback mechanisms modulation[28]. Alternatively, ionchan- kinases and corresponding dephospho- exist that modulate the electrophysiolog- nels may be regulated indirectly through rylation by phosphatases have been most ical properties of the heart in response mechanosensitive proteins such as poly- extensively studied [8, 20]. Given the to changes in intracellular Ca2+ lev- cystin 1, which increases the stability of relatively unspecific nature of phos- els. Calmodulin is a multifunctional L-type Ca2+ channels in response to me- phorylation the individual signaling Ca2+-binding messenger protein ex- chanical stretch [16]. As such, the com- components need to be highly localized pressed ubiquitously in all cells [25]. It position of the macromolecular com- in order to enable specific regulation of is a common constituent of ion channel plex may also modulate mechanosensi- individual targets. A-kinase anchoring macromolecular complexes and plays tive regulation. Finally, modulation of proteins (AKAPs) are a family of struc- an integral role in the Ca2+-dependent the mechanosensitive regulation of these turally diverse proteins that bind kinases regulation of these channels [25]. For ex- channels by antiarrhythmic drugs, as has and phosphatases and anchor them to ample, Ca2+ influx through L-type Ca2+ been identified for ranolazine and Na+ the macromolecular ion channel com- channels undergoes strong autoregu- channels [29], may influence their an- plexes [21]. For example, the targeting lation through Ca2+-dependent inacti- tiarrhythmic efficacy. of protein kinase A (PKA) to the IKs vation of the channel, which critically macromolecular complex by the AKAP dependsontheinteractionofcalmodulin Clinical relevance Yotiao is essential for the upregulation of with the C-terminus of the pore-forming IKs in response to β-adrenoceptor stimu- α subunit [25]. Similarly, calmodulin Numerous mutations in cardiac ion lation (. Fig. 2b;[9, 22]). Similarly, PKA binds to RyR2 and stabilizes its gating channels and Ca2+-handling proteins is targeted to the RyR2 macromolecu- [26]. Accumulating data indicate that have been identified that lead to ar- lar complex via mAKAP, although the also non-Ca2+ channels can undergo rhythmia syndromes. Several of these functional relevance of PKA-dependent Ca2+-dependent regulation mediated by mutations disrupt the macromolecular RyR2 regulation remains a topic of de- calmodulin in their macromolecular complex composition and subsequently bate [10, 23]. In addition to kinases and complex. These include Na+ channels, promote dysregulation of ion channel

Herzschrittmachertherapie + Elektrophysiologie 1 · 2018 33 Schwerpunkt

function, contributing to their geno- contribute to RyR2 dysfunction and for further research remain. For exam- type–phenotype relationship [3, 30]. subsequent triggered activity in these ple, information about the stoichiometry For example, loss-of-function muta- patients [33]. By contrast, RyR2 dys- and temporal variability in the compo- tions in the pore-forming α-subunit function in patients with long-standing sition of macromolecular complexes is Kv7.1, β-subunit KCNE1 and the AKAP persistent AF has been attributed to limited. Similarly, the dynamic remod- Yotiao have been identified that disrupt RyR2 hyperphosphorylation [34]and eling of macromolecular complexes in the IKs macromolecular complex and preliminary data suggest that this might response to cardiovascular disease is thereby prevent PKA-dependent phos- be due to an imbalance in kinase and incompletely characterized, particularly phorylation of Kv7.1 and subsequent phosphatase levels within the macro- in human cardiomyocytes. Finally, there upregulation of IKs during sympathetic molecular complex [35]. Similarly, the are currently almost no (therapeutic) in- stimulation [9, 22]. Carriers of these increased relative amount of protein terventions to selectively and reversibly mutations have long-QT syndrome and kinase C within the NCX1 macro- alter the interactions between differ- are at an increased risk for ventricular molecular complex of long-standing ent components of a macromolecular tachyarrhythmias, particularly during persistent AF patients may contribute complex. A better understanding of conditions of elevated sympathetic tone. to the increase in NCX1 activity that the composition and clinical relevance Similarly, mutations in RyR2 and its also promotes proarrhythmic triggered of ion channel macromolecular com- interacting proteins (e. g., calmodulin, activity in these patients [36]. Thus, plexes and the subsequent development calsequestrin 2, and junctophilin 2) have both genetic and acquired changes in of new therapeutic options based on this been identified that disrupt the inter- macromolecular complex composition knowledge is expected to enable a more action with these stabilizing regulators, may promote cardiac arrhythmias. effective, mechanism-based treatment of promoting aberrant RyR2 gating and pre- heart rhythm disorders. disposing patients to catecholaminergic Conclusions and future polymorphic ventricular tachycardia perspectives Corresponding address and/or familial atrial fibrillation (AF; [1, Dr. J. Heijman 30, 31]). Finally, the phospholamban The tightly controlled regulation of ion Department of Cardiology, Cardiovascular Arg14del mutation, which predisposes channel function plays a critical role Research Institute Maastricht, Faculty of patients to a severe arrhythmogenic car- in cardiac (patho)physiology. Macro- Health, Medicine, and Life Sciences, Maastricht diomyopathy, produces a remarkable molecular complexes are essential for this University change in macromolecular complexes in regulation by bringing together pore- 616, 6200 Maastricht, The Netherlands [email protected] mice by switching from the SERCA2a forming and regulatory subunits, pro- macromolecular complex to the Na+-K+- teins controlling ion channel trafficking Dr. D. Dobrev ATPase complex [32], highlighting the and localization, kinases, phosphatases Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, intricate regulation of macromolecular and other components of signaling path- University Duisburg-Essen complex composition. ways,aswellasproteinsinvolvedinother Hufelandstr. 55, 45122 Essen, Germany In addition to genetic variants that forms of ion channel regulation (e. g., [email protected] perturb protein–protein interactions, Ca2+-dependent regulation). Mutations dysfunction of macromolecular com- that disrupt the physiological interaction Funding. The authors’ work is supported by the plexes can result from an imbalanced of components of the macromolecular Netherlands Organization for Scientific Research expression of individual components or complexorchangesintherelativepro- (ZonMW Veni 91616057 to J.H.), the CardioVascular Onderzoek Nederland (CVON) and Netherlands altered binding affinities due to cardio- tein expression or binding affinities of Heart Foundation PREDICT project (Young Talent vascular disease (. Fig. 2a). Although these components can alter ion channel Program to J.H.), the National Institutes of Health there is limited information about the function and have been implicated in (R01-HL131517 and R01-HL136389 to D.D.), the DZHK (German Center for Cardiovascular Research, dynamic changes in macromolecular arrhythmogenesis. Here, we have fo- 81X2800108, 81X2800161, and 81X2800136 to D.D.) complex composition during cardiovas- cused on protein–protein interactions and the German Research Foundation (DFG, Do cular diseases in humans, recent data occurring within a single cardiomyocyte, 769/4-1 to D.D.). haveprovidedseveralexamplesofmacro- but macromolecular complexes are sim- molecular complex dysregulation in AF ilarly involved in cell–cell adhesion and Compliance with ethical patients. For example, in paroxysmal AF intercellular communication, and dys- guidelines patients, the expression of RyR2 was in- function of these complexes may also creased, but expression of junctophilin 2 contribute to arrhythmogenesis (e. g., in Conflict of interest. J.HeijmanandD.Dobrevdeclare was unchanged [31]. Furthermore, RyR2 arrhythmogenic right ventricular car- that they have no competing interests. single-channel activity was enhanced in diomyopathies) [37]. This article does not contain any studies with human the absence of increased RyR2 phos- Although the understanding about participants or animals performed by any of the au- phorylation, suggesting that a relative macromolecular complexes and their thors. The ethical guidelines of the studies cited in this deficiency of stabilizing junctophilin 2 clinical relevance has increased signifi- article can be found in each study. in the macromolecular complex may cantly in recent years, numerous topics

34 Herzschrittmachertherapie + Elektrophysiologie 1 · 2018 OpenAccess. Thisarticleisdistributedundertheterms membrane protein targeting pathways underlie Ca2+ leak and increased Na+-Ca2+ exchanger of the Creative Commons Attribution 4.0 International atrialfibrillation. Circulation124(11):1212–1222 function underlie delayed after depolarizations in License (http://creativecommons.org/licenses/by/ 17. Smith SA, Sturm AC, Curran J, Kline CF, Little patients with chronic atrial fibrillation. Circulation 4.0/), which permits unrestricted use, distribution, SC, Bonilla IM et al (2015) Dysfunction in the 125(17):2059–2070 and reproduction in any medium, provided you give betaII spectrin-dependent cytoskeleton underlies 35. Schirmer IM, Heijman J, Voigt N, Dobrev D (2015) appropriate credit to the original author(s) and the humanarrhythmia. Circulation131(8):695–708 Altered composition of the ryanodine receptor source, providealinktotheCreativeCommonslicense, 18. Pedrozo Z, Criollo A, Battiprolu PK, Morales CR, channel complex in patients with chronic atrial and indicate if changes were made. Contreras-Ferrat A, Fernandez C et al (2015) fibrillation(Abstract). HeartRhythm12(5):1–S50 Polycystin-1 is a cardiomyocyte mechanosensor 36. Ghezelbash S, Molina CE, Badimon L, Kamler thatgoverns L-type Ca2+ channelproteinstability. M, Heijman J, Dobrev D (2016) Abstract 12860: References Circulation131(24):2131–2142 enhanced expression and PKCδ-mediated hy- 19. Gonzalez DR, Treuer A, Sun QA, Stamler JS, Hare perphosphorylation underlie the proarrhythmic 1. Landstrom AP, Dobrev D, Wehrens XHT (2017) JM (2009) S-Nitrosylation of cardiac ion channels. increase in Na+-Ca2+ exchanger activity in pa- Calcium signaling and cardiac arrhythmias. Circ JCardiovascPharmacol54(3):188–195 tients with chronic atrial fibrillation. Circulation Res120(12):1969–1993 20. Heijman J, Dewenter M, El-Armouche A, Dobrev D 134(Suppl1):A12860 2. Bartos DC, Grandi E, Ripplinger CM (2015) (2013)Functionandregulationofserine/threonine 37. Rampazzo A, Calore M, van Hengel J, van Roy F Ion channels in the heart. Compr Physiol phosphatases in the healthy and diseased heart. (2014) Intercalated discs and arrhythmogenic car- 5(3):1423–1464 J Mol Cell Cardiol 64:90–98 diomyopathy. CircCardiovascGenet7(6):930–940 3. Abriel H, Rougier JS, Jalife J (2015) Ion chan- 21. Soni S, Scholten A, Vos MA, van Veen TA (2014) nel macromolecular complexes in cardiomy- Anchored protein kinase A signalling in cardiac ocytes: roles in sudden cardiac death. Circ Res cellular electrophysiology. J Cell Mol Med 116(12):1971–1988 18(11):2135–2146 4. Molina CE, Heijman J, Dobrev D (2016) Differences 22. ChenL,KassRS(2011)A-kinaseanchoringprotein9 in left versus right ventricular electrophysio- andIKs channelregulation. JCardiovascPharmacol logical properties in cardiac dysfunction and 58(5):459–413 arrhythmogenesis. Arrhythm Electrophysiol Rev 23. Dobrev D, Wehrens XH (2014) Role of RyR2 5(1):14–19 phosphorylation in heart failure and arrhyth- 5. Heijman J, Algalarrondo V, Voigt N, Melka J, mias: controversies around ryanodine receptor Wehrens XH, Dobrev D et al (2016) The value phosphorylation in cardiac disease. Circ Res of basic research insights into atrial fibrillation 114(8):1311–1319 mechanisms as a guide to therapeutic innovation: 24. VikramA,LewarchikCM,YoonJY,NaqviA,KumarS, acriticalanalysis. CardiovascRes109(4):467–479 Morgan GM et al (2017) Sirtuin 1 regulates cardiac 6. HulmeJT,ScheuerT,CatterallWA(2004)Regulation electrical activity by deacetylating the cardiac of cardiac ion channels by signaling complexes: sodiumchannel. NatMed23(3):361–367 role of modified leucine zipper motifs. J Mol Cell 25. Sorensen AB, Sondergaard MT, Overgaard MT Cardiol37(3):625–631 (2013) Calmodulin in a heartbeat. Febs J 7. Rougier JS, Abriel H (1863) Cardiac voltage-gated 280(21):5511–5532 calcium channel macromolecular complexes. 26. Hwang HS, Nitu FR, Yang Y, Walweel K, Pereira L, BiochimBiophysActa7PtB:1806–1812 Johnson CN et al (2014) Divergent regulation of 8. Grandi E, Sanguinetti MC, Bartos DC, Bers DM, ryanodine receptor 2 calcium release channels Chen-Izu Y, Chiamvimonvat N et al (2017) Potas- by arrhythmogenic humancalmodulinmissense siumchannels in the heart:structure, function and mutants. CircRes114(7):1114–1124 regulation. JPhysiol595(7):2209–2228 27. Shaikh SA, Sahoo SK, Periasamy M (2016) 9. HeijmanJ,DobrevD(2013)KCNQ1autoantibodies: Phospholamban and sarcolipin: are they func- another way to regulate IKs. Cardiovasc Res tionally redundant or distinct regulators of the 98(3):329–331 sarco(endo)plasmic reticulum calcium ATPase? 10. Marks AR, Marx SO, Reiken S (2002) Regulation J Mol Cell Cardiol 91:81–91 of ryanodine receptors via macromolecular 28. Peyronnet R, Nerbonne JM, Kohl P (2016) Cardiac complexes: a novel role for leucine/isoleucine mechano-gated Ion channels and arrhythmias. zippers. TrendsCardiovascMed12(4):166–170 CircRes118(2):311–329 11. Balse E, Steele DF, Abriel H, Coulombe A, 29. Beyder A, Strege PR, Reyes S, Bernard CE, Terzic Fedida D, Hatem SN (2012) Dynamic of ion A, Makielski J et al (2012) Ranolazine decreases channel expression at the plasma membrane of mechanosensitivity of the voltage-gated sodium cardiomyocytes. PhysiolRev92(3):1317–1358 ion channel Na(v)1.5: a novel mechanism of drug 12. Basheer WA, Shaw RM (2016) Connexin 43 action. Circulation125(22):2698–2706 and CaV1.2 ion channel trafficking in healthy 30. El-Sherif N, Boutjdir M (2015) Role of phar- and diseased myocardium. Circ Arrhythm macotherapy in cardiac ion channelopathies. Electrophysiol9(6):e1357 PharmacolTher155:132–142 13. Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon 31. Beavers DL, Wang W, Ather S, Voigt N, Garbino A, JE et al (2001) Regulation of KChIP2 potassium DixitSSetal(2013)MutationE169Kinjunctophilin- channel beta subunit gene expression underlies 2 causes atrial fibrillation due to impaired RyR2 thegradientoftransientoutwardcurrentincanine stabilization. JAmCollCardiol62(21):2010–2019 andhumanventricle. JPhysiol533(Pt1):119–125 32. Haghighi K, Pritchard T, Bossuyt J, Waggoner 14. Steele DF, Fedida D (2014) Cytoskeletal roles in JR, Yuan Q, Fan GC et al (2012) The human cardiac ion channel expression. Biochim Biophys phospholamban Arg14-deletion mutant localizes Acta1838(2):665–673 to plasma membrane and interacts with the Na/K- 15.ShyD,GilletL,OgrodnikJ,AlbesaM,VerkerkAO, ATPase. JMolCellCardiol52(3):773–782 Wolswinkel R et al (2014) PDZ domain-binding 33. Voigt N, Heijman J, Wang Q, Chiang DY, Li N, motif regulates cardiomyocyte compartment- Karck M et al (2014) Cellular and molecular specific NaV1.5 channel expression and function. mechanismsofatrialarrhythmogenesisinpatients Circulation130(2):147–160 with paroxysmal atrial fibrillation. Circulation 16.CunhaSR,HundTJ,HashemiS,VoigtN,LiN, 129(2):145–156 Wright P et al (2011) Defects in ankyrin-based 34. VoigtN,LiN,WangQ,WangW, TraffordAW, Abu- TahaIetal(2012)Enhancedsarcoplasmicreticulum

Herzschrittmachertherapie + Elektrophysiologie 1 · 2018 35