Transmural Gradients of Repolarization and Excitation–Contraction Coupling in Mouse Ventricle
2006; Lippincott Williams & Wilkins; Volume: 98; Issue: 10 Linguagem: Inglês
10.1161/01.res.0000225859.82676.ba
ISSN1524-4571
Autores Tópico(s)Neuroscience and Neural Engineering
ResumoHomeCirculation ResearchVol. 98, No. 10Transmural Gradients of Repolarization and Excitation–Contraction Coupling in Mouse Ventricle Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTransmural Gradients of Repolarization and Excitation–Contraction Coupling in Mouse Ventricle Céline Fiset and Wayne R. Giles Céline FisetCéline Fiset From the Research Center (C.F.), Montreal Heart Institute, Quebec, Canada; and the Departments of Bioengineering and Medicine (W.R.G.), University of California San Diego, La Jolla, Calif. and Wayne R. GilesWayne R. Giles From the Research Center (C.F.), Montreal Heart Institute, Quebec, Canada; and the Departments of Bioengineering and Medicine (W.R.G.), University of California San Diego, La Jolla, Calif. Originally published26 May 2006https://doi.org/10.1161/01.RES.0000225859.82676.baCirculation Research. 2006;98:1237–1239The effects of changes in action potential waveform on excitation–contraction coupling in mammalian ventricle were first identified almost 40 years ago.1 Many important details concerning the relationship between action potential duration and tension development have been elucidated.2 Recent work has demonstrated significant effects on the intracellular Ca transient and excitation–contraction coupling of early repolarization of the action potential, which is strongly regulated by a Ca2+-independent transient outward K+ current denoted Ito.3–6 The molecular physiology and some aspects of the pharmacology of this current are now quite well understood, based, in part, on a series of comprehensive articles from the Nerbonne et al,7,8 Strauss and Campbell,9 and others.6 Interestingly, a somewhat similar transient outward K+ current is expressed in neurons10 and in selected regions near the intraventricular septum of mammalian hearts.11–13One of the most striking features of the transient outward K+ current in mammalian ventricle is the difference in its transmural expression, with significantly higher expression levels in epi- than in endocardium14 (see also references 8, 9, 11). The basis for this transmural heterogeneity, and also for the higher levels of expression in the right ventricle compared with the left, continues to be a topic of intense investigation. Significant new information and plausible working hypotheses for the way in which this heterogeneity can regulate excitation–contraction coupling are a focus of work from the laboratory of Santana et al.15 Their most recent article is published in this issue of Circulation Research.16 This article provides new evidence for the ways in which the calcineurin/NFATc3 signalling complex can contribute to the transmural gradient of Ito in the left ventricle of the adult mouse heart.The magnitude of Ito, Kv4.2, and Kv4.3 have been reported to be reduced by both acute and long-term activation of various receptor-mediated pathways in response to neurohormonal factors. Moreover, gene transfer technology has provided new insights concerning the role of Ito, Kv4.2, and Kv4.3 in the hypertrophic response.6,17,18 A number of lines of evidence suggest that the reduction of Ito (and of Kv4.2 and Kv4.3) can prolong APD, increase Ca2+ entry via ICaL, and activate calcineurin phosphatase activity. Calcineurin in turn dephosphorylates NFAT which is in the cytosol. Once dephosphorylated, NFAT can translocate into the nucleus and (with several other factors) can activate transcription and protein synthesis.6,16,17 Accordingly, these studies have suggested that prolongation of APD can result in protein synthesis and contribute to a hypertrophic response or other forms of adaptation. In contrast, the present article by Rossow et al16 concludes that the activation of the calcineurin pathway occurs before changes in Kv4.2/Ito in mouse ventricle and that this is a significant causative factor in the transmural heterogeneity of APD.Alternate biochemical pathways which contribute to this heterogeneity have been identified previously. These include contributions from a homeodomain transcription factor Irx5,19 the KChIPs beta subunit for Kv4.2, 4.3,8,9,20–22 and association with the CD26-related dipeptidyl aminopeptidase-like protein, DPPX.23–25Attempts to place the elegant work by the Santana laboratory16 into the context of the pathophysiological mechanisms for excitation-contraction coupling in the left ventricle will require some additional work and integration of a number of important considerations. These include: Action potential duration in general and the part of the waveform most strongly regulated by Ito are dependent on transient or maintained heart rate or stimulus frequency. The experiments in Rossow et al16 have been done at 1 Hz which is far below normal mouse heart rates. Thus, ECG parameters,26,27 action potential waveforms,27,28 and relative sizes of underlying repolarizing currents29 are difficult to relate to findings from the hearts of larger mammals. Furthermore, repolarization of the action potential of mouse ventricle is strongly modulated by Kv1.5,8,29,30 and this transcript is not expressed in the ventricles of other mammals.The present work needs to be put into the context of both short and long-term hormonal regulation of Ito. Specifically, previous work demonstrating an important role of the renin–angiotensin system in regulating Ito31,32 needs to be considered as do the findings which demonstrate that thyroid hormone can alter transmural heterogeneity.33,34It is reasonable to expect that in the setting of a variety of short- or long-term pathophysiological insults the tissue redox status will be altered. This specifically free radical generation is known to modulate the size and kinetics of Ito, which may account for some of the changes in this current in the setting of Diabetes34,35 or a variety of other situations where mitogen activation of intracellular cell signaling is important.36Factors other than the way in which Ito regulates the action potential waveform in the mouse heart or early repolarization in mammalian ventricle should be borne in mind. For example, it is known that Ito can modulate intercellular coupling and result in discontinuous conduction in rabbit ventricle,37 and somewhat similar alterations in electrotonic load can result in altered Ito amplitude.38The calcineurin/NFAT pathway for regulation of Ito has been invoked in pacing-induced cardiac remodeling40 as well as after myocardial infarction.42 However, significant reprogramming of ion channel genes occurs after these and other challenges.41 The adult myocardium can approximate the electrophysiological phenotype found in early development.43 The K+ channel alpha subunit, Kv1.4, can thus contribute significant repolarizing current under these circumstances but has not been shown to be altered by the biochemical pathways which have been the focus of the work of Santana et al,16 interesting and important mechanistic questions remain.These comments reflect the reality that repolarization and specifically the all-or-none repolarization which underlies APD heterogeneity and dispersion is extremely complex. The Santana et al article is based on comprehensive and elegant multidisciplinary work. It provides significant new information concerning one component of this complex multifactorial process: excitation–contraction coupling. Ongoing experimental work will benefit from the parallel development of mathematical models for the action potential44–46 of the species and myocytes of interest. The ability to integrate multidisciplinary findings using Systems Biology will be valuable. Mathematical models provide a means for incorporating and evaluating essential biophysical phenomena. These include: the partial reactivation of Ito during mid and final repolarization9 and the dynamic regulation of the Na+/Ca2+ exchanger by altered Na+ or Ca2+, and by transmembrane voltage47 (see also reference 3). These nonlinear processes must be accounted for and related to the other essential steps in ventricular Ca2+ homeostasis which contribute to excitation–contraction coupling under physiological conditions, eg, sympathetic neurotransmission,48,49 and in the setting of ventricular challenge or compromise.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Funding is gratefully acknowledged from the Canadian Institutes of Health Research and the National Institutes of Health.FootnotesCorrespondence to Wayne R. Giles, PhD, Professor, Departments of Bioengineering and Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412. E-mail [email protected] References 1 Wood EH, Heppner R, Wiedmann S. Inotropic effects of electric currents. Circ Res. 1969; 24: 409–445.CrossrefMedlineGoogle Scholar2 Allen DG. On the relationship between action potential duration and tension in cat papillary muscle. Cardiovasc Res. 1977; 11: 210–218.CrossrefMedlineGoogle Scholar3 Clark RB, Bouchard RA, Giles WR. Action potential duration modulates calcium influx, Na+-Ca2+ exchange, and intracellular calcium release in rat ventricular myocytes. Ann N Y Acad Sci. 1996; 779: 417–429.CrossrefMedlineGoogle Scholar4 Volk T, Nguyen TH, Schultz JH, Ehmke H. Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin. J Physiol. 1999; 519: 841–850.CrossrefMedlineGoogle Scholar5 Sah R, Ramirez RJ, Oudit GY, Gidrewicz D, Trivieri MG, Zobel C, Backx PH. Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (I(to)). J Physiol. 2003; 546: 5–18.CrossrefMedlineGoogle Scholar6 Oudit GY, Kassiri Z, Sah R, Ramirez RJ, Zobel C, Backx PH. The molecular physiology of the cardiac transient outward potassium current (Ito) in normal and diseased myocardium. J Mol Cell Cardiol. 2001; 33: 851–872.CrossrefMedlineGoogle Scholar7 Nerbonne JM. Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol. 2000; 525: 285–298.CrossrefMedlineGoogle Scholar8 Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev. 2005; 85: 1205–1253.CrossrefMedlineGoogle Scholar9 Patel SP, Campbell DL. Transient outward potassium current, 'Ito', phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms. J Physiol. 2005; 569: 7–39.CrossrefMedlineGoogle Scholar10 Jerng HH, Pfaffinger PJ, Covarrubias M. Molecular physiology and modulation of somatodendritic A-type potassium channels. Mol Cell Neurosci. 2004; 27: 343–369.CrossrefMedlineGoogle Scholar11 Brunet S, Aimond F, Li H, Guo W, Eldstrom J, Fedida D, Yamada KA, Nerbonne JM. Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult mouse ventricles. J Physiol. 2004; 559: 103–120.CrossrefMedlineGoogle Scholar12 Wickenden AD, Jegla TJ, Kaprielian R, Backx PH. Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K currents in rat ventricle. Am J Physiol. 1999; 45: H1599–H1607.Google Scholar13 Giles W, Clark RB, Braun A. Ca2+-independent transient outward current in mammalian heart. In: Molecular Physiology and Pharmacology of Cardiac Ion Channels and Transporters, Morad M, Kurachi Y, Noma A, Hosada M, eds. Amsterdam: Kluwer Press Ltd; 1996: 141–168.Google Scholar14 Antzelevitch C, Dumaine R. Electrical heterogeneity in the heart: physiological, pharmacological and clinical implication. In: Handbook of Physiology. Fozzard HA, Solaro RJ, eds. New York: Oxford University Press; 2001.Google Scholar15 Dilly KW, Rossow CF, Votaw VS, Meabon JS, Cabarrus JL, Santana LF. Mechanisms underlying variations in excitation-contraction coupling across the mouse left ventricular free wall. J Physiol. 2006; 572: 227–241.CrossrefMedlineGoogle Scholar16 Rossow CF, Dilly KW, Santana LF. Differential calcineurin/NFATc3 activity contributes to the Ito transmural gradient in the mouse heart. Circ Res. 2006; 98: 1306–1313.LinkGoogle Scholar17 Sah R, Oudit GY, Nguyen TT, Lim HW, Wickenden AD, Wilson GJ, Molkentin JD, Backx PH. Inhibition of calcineurin and sarcolemmal Ca2+ influx protects cardiac morphology and ventricular function in Kv4.2N transgenic mice. Circulation. 2002; 105: 1850–1856.LinkGoogle Scholar18 Lebeche D, Kaprielian R, del Monte F, Tomaselli G, Gwathmey JK, Schwartz A, Hajjar RJ. In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis. Circulation. 2004; 110: 3435–3443.LinkGoogle Scholar19 Costantini DL, Arruda EP, Agarwal P, Kim KH, Zhu Y, Zhu W, Lebel M, Cheng CW, Park CY, Pierce SA, Guerchicoff A, Pollevick GD, Chan TY, Kabir MG, Cheng SH, Husain M, Antzelevitch C, Srivastava D, Gross GJ, Hui CC, Backx PH, Bruneau BG. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Cell. 2005; 123: 347–358.CrossrefMedlineGoogle Scholar20 Deschenes I, Tomaselli GF. Modulation of Kv4.3 current by accessory subunits. FEBS Lett. 2002; 528: 183–188.CrossrefMedlineGoogle Scholar21 Decher N, Barth AS, Gonzalez T, Steinmeyer K, Sanguinetti MC. Novel KChIP2 isoforms increase functional diversity of transient outward potassium currents. J Physiol. 2004; 557: 761–772.CrossrefMedlineGoogle Scholar22 Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguyen-Tran VT, Gu Y, Ikeda Y, Chu PH, Ross J, Giles WR, Chien KR. A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell. 2001; 107: 801–813.CrossrefMedlineGoogle Scholar23 Jerng HH, Kunjilwar K, Pfaffinger PJ. Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties. J Physiol. 2005; 568: 767–788.CrossrefMedlineGoogle Scholar24 Zagha E, Ozaita A, Chang SY, Nadal MS, Lin U, Saganich MJ, McCormack T, Akinsanya KO, Qi SY, Rudy B. DPP10 modulates Kv4-mediated A-type potassium channels. J Biol Chem. 2005; 280: 18853–18861.CrossrefMedlineGoogle Scholar25 Radicke S, Cotella D, Graf EM, Ravens U, Wettwer E. Expression and function of dipeptidyl-aminopeptidase-like protein 6 as a putative beta-subunit of human cardiac transient outward current encoded by Kv4.3. J Physiol. 2005; 565: 751–756.CrossrefMedlineGoogle Scholar26 Danik S, Cabo C, Chiello C, Kang S, Wit AL, Coromilas J. Correlation of repolarization of ventricular monophasic action potential with ECG in the murine heart. 2002; 283: H372–H381.Google Scholar27 Liu G, Iden JB, Kovithavongs K, Gulamhusein R, Duff HJ, Kavanagh KM. In vivo temporal and spatial distribution of depolarization and repolarization and the illusive murine T wave. J Physiol. 2003; 555: 267–279.MedlineGoogle Scholar28 Knollmann BC, Katchman AN, Franz MR. Monophasic action potential recordings from intact mouse heart: validation, regional heterogeneity, and relation to refractoriness. J Cardiovasc Electrophysiol. 2001; 12: 1286–1294.CrossrefMedlineGoogle Scholar29 Brouillette J, Clark RB, Giles WR, Fiset C. Functional properties of K+ currents in adult mouse ventricular myocytes. J Physiol. 2004; 559: 777–798.CrossrefMedlineGoogle Scholar30 Fiset C, Clark RB, Larsen TS, Giles WR. A rapidly activating sustained K+ current modulates repolarization and excitation-contraction coupling in adult mouse ventricle. J Physiol. 1997; 504: 557–563.CrossrefMedlineGoogle Scholar31 Yu H, Gao J, Wang H, Wymore R, Steinberg S, McKinnon D, Rosen MR, Cohen IS. Effects of the renin-angiotensin system on the current I(to) in epicardial and endocardial ventricular myocytes from the canine heart. Circ Res. 2000; 86: 1062–1068.CrossrefMedlineGoogle Scholar32 Delpon E, Caballero R, Gomez R, Nunez L, Tamargo J. Angiotensin II, angiotensin II antagonists and spironolactone and their modulation of cardiac repolarization. Trends Pharmacol Sci. 2005; 26: 155–161.CrossrefMedlineGoogle Scholar33 Shimoni Y, Fiset C, Clark RB, Giles WR. Thyroid hormone regulates postnatal expression of transient K+ channel isoforms in rat ventricle. J Physiol. 1997; 500: 65–73.CrossrefMedlineGoogle Scholar34 Shimoni Y, Severson D, Giles W. Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle. J Physiol. 1995; 488: 673–688.CrossrefMedlineGoogle Scholar35 Li X, Li S, Xuy Z, Lou MF, Anding P, Liu D, Roy SK, Rozanski GJ. Redox control of K+ channel remodeling in rat ventricle. J Mol Cell Cardiol. 2006; 40: 339–340.CrossrefMedlineGoogle Scholar36 Jia Y, Takimoto K. Mitogen-activated protein kinases control cardiac KChIP2 gene expression. Circ Res. 2006; 98: 386–393.LinkGoogle Scholar37 Thorneloe KS, Liu XF, Walsh MP, Shimoni Y. Transmural differences in rat ventricular protein kinase C epsilon correlate with its functional regulation of a transient cardiac K+ current. J Physiol. 2001; 533: 145–154.CrossrefMedlineGoogle Scholar38 Huelsing DJ, Pollard AE, Spitzer KW. Transient outward current modulates discontinuous conduction in rabbit ventricular cell pairs. Cardiovas Res. 2001; 49: 769–779.Google Scholar39 Libbus I, Wan X, Rosenbaum DS. Electrotonic load triggers remodeling of repolarizing current Ito in ventricle. Am J Physiol Heart Circ Physiol. 2004; 286: H1901–H1909.CrossrefMedlineGoogle Scholar40 Tavi P, Pikkarainen S, Ronkainen J, Niemela P, Ilves M, Weckstrom M, Vuolteenaho O, Bruton J, Westerblad H, Ruskoaho H. Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression. J Physiol. 2004; 554: 309–320.CrossrefMedlineGoogle Scholar41 Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature. 1997; 386: 855–858.CrossrefMedlineGoogle Scholar42 Rossow CF, Minami E, Chase EG, Murry CE, Santana LF. NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction. Circ Res. 2004; 94: 1340–1350.LinkGoogle Scholar43 Wang L, Duff HJ. Developmental changes in transient outward current in mouse ventricle. Circ Res. 1997; 81: 120–127.CrossrefMedlineGoogle Scholar44 Greenstein JL, Wu R, Po S, Tomaselli GF, Winslow RL. Role of the calcium-independent transient outward current Ito in shaping action potential morphology and duration. Circ Res. 2000; 87: 1026–1033.CrossrefMedlineGoogle Scholar45 Pandit SV, Giles WR, Demir SS. A mathematical model of the electrophysiological alterations in rat ventricular myocytes in Type-I diabetes. Biophys J. 2003; 84: 832–841.CrossrefMedlineGoogle Scholar46 Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol. 2004; 287: H1378–H1403.CrossrefMedlineGoogle Scholar47 Bridge JHB, Smolley J, Spitzer KW, Chin TK. Voltage dependence of sodium-calcium exchange and the control of calcium extrusion in the heart. Ann N Y Acad Sci. 1991; 639: 34–47.CrossrefMedlineGoogle Scholar48 Fedida D. Modulation of cardiac contractility by alpha 1 adrenoceptors. Cardiovasc Res. 1993; 27: 1735–1742.CrossrefMedlineGoogle Scholar49 Vinogradova TM, Lyashkov AE, Zhu W, Ruknudin AM, Sirenko S, Yang D, Deo S, Barlow M, Johnson S, Caffrey JL, Zhou YY, Xiao RP, Cheng H, Stern MD, Maltsev VA, Lakatta EG. High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells. Circ Res. 2006; 98: 505–514.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kim K, Oh Y, Liu J, Dababneh S, Xia Y, Kim R, Kim D, Ban K, Husain M, Hui C and Backx P (2022) Irx5 and transient outward K + currents contribute to transmural contractile heterogeneities in the mouse ventricle , American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00572.2021, 322:5, (H725-H741), Online publication date: 1-May-2022. Liu J, Kim K, Morales M, Heximer S, Hui C, Backx P and Rota M (2015) Kv4.3-Encoded Fast Transient Outward Current Is Presented in Kv4.2 Knockout Mouse Cardiomyocytes, PLOS ONE, 10.1371/journal.pone.0133274, 10:7, (e0133274) Saint D, Kelly D and Mackenzie L (2010) The Contribution of MEF to Electrical Heterogeneity and Arrhythmogenesis Mechanosensitivity of the Heart, 10.1007/978-90-481-2850-1_11, (275-300), . Bondarenko V and Rasmusson R (2007) Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00471.2007, 293:3, (H1816-H1832), Online publication date: 1-Sep-2007. Teutsch C, Kondo R, Dederko D, Chrast J, Chien K and Giles W (2007) Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection, Cardiovascular Research, 10.1016/j.cardiores.2006.11.034, 73:4, (739-749), Online publication date: 1-Mar-2007. Killeen M, Thomas G, Gurung I, Goddard C, Fraser J, Mahaut-Smith M, Colledge W, Grace A and Huang C (2007) Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart, Acta Physiologica, 10.1111/j.1748-1716.2006.01643.x, 189:1, Online publication date: 1-Jan-2007. May 26, 2006Vol 98, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000225859.82676.baPMID: 16728668 Originally publishedMay 26, 2006 KeywordsKv4.2/4.3K channel beta subunitstransmural repolarizationPDF download Advertisement
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