Sticky Fingers
2009; Lippincott Williams & Wilkins; Volume: 104; Issue: 6 Linguagem: Inglês
10.1161/circresaha.109.195503
ISSN1524-4571
Autores Tópico(s)Neuroscience and Neuropharmacology Research
ResumoHomeCirculation ResearchVol. 104, No. 6Sticky Fingers Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSticky FingersCaMKII Finds a Home on Another Ion Channel Mark E. Anderson Mark E. AndersonMark E. Anderson From the Department of Internal Medicine, Division of Cardiovascular Medicine, Carver College of Medicine, University of Iowa, Iowa City. Originally published27 Mar 2009https://doi.org/10.1161/CIRCRESAHA.109.195503Circulation Research. 2009;104:712–714The multifunctional Ca2+ and calmodulin dependent protein kinase (CaMK)II is a serine threonine kinase that plays increasingly evident and important roles in regulating ion channels in heart and other excitable tissues. CaMKII activation initially requires an increase in intracellular Ca2+ that leads to binding of calcified calmodulin (Ca2+/CaM) to the CaMKII regulatory domain. This activating Ca2+/CaM signal is amplified within the CaMKII holoenzyme, which is composed of 10 to 12 monomers arranged in a wheel and spoke pattern (Figure, A), by an autophosphorylation process. Autophosphorylation of Thr286/287 (numbering varies by isoform) markedly increases the avidity of Ca2+/CaM binding to CaMKII but also renders CaMKII constitutively active even in the absence of Ca2+/CaM binding.1 Autophosphorylation of Thr286/287 prevents the reassociation of the autoinhibitory region with the CaMKII catalytic domain, leaving the autophosphorylated kinase in the open and active configuration. Reactive oxygen species modify a pair of methionines (281/282) near the autophosphorylation site to convert CaMKII activity from Ca2+/CaM-dependent to Ca2+/CaM-independent by a process that mirrors autophosphorylation (Figure, A).2 In this issue of Circulation Research, El-Haou et al3 have provided exciting new insights into the association of CaMKII with the MAGUK protein SAP97 by showing that a PDZ motif on the C terminus of KV4.3 partners with the SAP97-CaMKII module to enable CaMKII-dependent gating effects on KV4.3 channels. CaMKII-mediated increases in the transient outward current (Ito) require binding of the SAP97-CaMKII module to the KV4.3 C terminus. These findings provide a molecular framework for understanding how excitable tissues tune repolarization to manage cellular Ca2+ entry. Download figureDownload PowerPointFigure. CaMKII activation favors action potential prolongation by increasing Ca2+ currents or action potential shortening by increasing K+ currents. A, The CaMKII holoenzyme and a single CaMKII subunit (top). The regulatory domain consists of an autoinhibitory region (AI) and a calmodulin binding region (CaM-B). CaMKII becomes constitutively active by autophosphorylation and/or oxidation (bottom). B, The relationship of CaMKII activation to Ca2+ current (ICa) and the transient outward K+ current (Ito) and action potential (AP) duration.Connecting Cellular Ca2+ With RepolarizationThe cardiac action potential is long (even in the atrium) compared to action potentials in other excitable tissues, and the action potential repolarization duration4 and configuration5 grade cellular Ca2+ entry through voltage-gated Ca2+ channels (ICa). ICa is mostly carried by CaV1.2 in ventricular myocardium and CaV1.2, CaV1.3, CaV3.1, and CaV3.2 in atrium and specialized conduction cells. CaMKII increases ICa through CaV1.2,6 CaV1.3,7 and CaV3.28 and most known intracellular Ca2+ homeostatic proteins are CaMKII substrates; therefore, CaMKII is appropriately positioned to serve as a master regulator of cellular Ca2+. CaMKII increases Ito to shorten the action potential duration and narrow the membrane potential window permissive for ICa. Thus, CaMKII activity at KV4.3 appears to balance the membrane potential and shorten the action potential to oppose the irrational exuberance of excessive CaMKII-mediated ICa increases (Figure, B), at least in healthy myocardium. CaMKII activity supports key physiological tasks in heart, such as excitation–contraction coupling,9 and fight or flight automaticity in sinoatrial nodal pacemaker cells.10 However, excessive CaMKII also contributes to the major diseases of myocardium: arrhythmias and heart failure, leading our group to consider CaMKII as a candidate therapeutic target for heart disease.11Connecting Cellular Ca2+ With Membrane ExcitabilityCaMKII can modulate membrane excitability by direct effects on Na+ current (INa) and via indirect effects on the Na+/Ca2+ exchanger (NCX). INa is mostly carried by NaV1.5 in cardiomyocytes, and CaMKII slows INa inactivation to prominently increase a small but important persistent or slow inactivating component of INa.12 CaMKII effects on NaV1.5 produce a INa phenocopy of a rare genetic arrhythmia syndrome (long QT syndrome 3)13 and of the increased persistent component of INa seen in heart failure.14 CaMKII activity is increased in heart failure,15 and an emerging body of evidence supports a view that NaV1.5 is an important pathological target that contributes to excessive action potential duration, arrhythmia-initiating afterdepolarizations, and subsarcolemmal Na+ loading that reduces the efficiency of the NCX for exporting cellular Ca2+ to the extracellular space.16 Whereas INa is required for normal membrane excitability in the atrial and ventricular myocardium, NCX current is associated with pathological automaticity in these cells.17,18 However, the NCX current is now recognized to play an important physiological role in membrane excitability in cardiac pacemaker cells,19 many of which lack INa. Thus, CaMKII is important for augmenting physiological and arrhythmogenic membrane excitability.Diversity of CaMKII Ion Channel PartnershipsCellular signaling systems have adapted mechanisms to guide key molecules into close proximity of target proteins. Highly defined localization profiles are an important mechanism for constraining signaling pathways and ensuring specificity. One common theme is for protein kinases to pair with phosphatases by adapter proteins that bring the kinase/phosphatase module to the immediate vicinity of target proteins. We see ultrastructural evidence that CaMKII is targeted to specific microdomains in cardiac myocytes,5 and the work of El-Haou et al shows that SAP97 can direct CaMKII signaling in atrial myocytes. In many cases, serine threonine kinases capable of regulating ion channels accomplish localization goals through specialized adapter proteins. In contrast, CaMKII seems not to have committed to a single localization strategy. CaMKII uses diverse approaches, including binding to sequences mimicking the autoinhibitory region of CaMKII itself. The CaMKII autoinhibitory domain is a pseudosubstrate for the catalytic domain and so sequences resembling the autoinhibitory domain have the potential to inhibit20 or anchor21 CaMKII by binding the catalytic domain.The CaV1.2 and CaV1.3 β subunits are MAGUK22 proteins like SAP97. There are 4 main β subunit genes, and each of these can encode a protein containing a conserved CaMKII phosphorylation site.23 This CaMKII phosphorylation site (Thr498 on β2a) is embedded within a primary sequence that is homologous to the CaMKII autoinhibitory domain in β1b and β2a. β1b and β2a bind CaMKII using these sequences. In fact, the position of Thr498 on β1b and β2a mirrors the relationship of the autophosphorylated Thr298 in the CaMKII autoinhibitory domain (Figure, A). CaMKII phosphorylation of Thr498 appears to be necessary for CaMKII effects on CaV1.2 pore-forming α subunits.21 Interestingly, CaMKII binding to CaV1 β subunits is dynamically regulated by Thr498 phosphorylation and by Thr286/287 autophosphorylation. Only autophosphorylated CaMKII binds the CaV1 β subunits, whereas phosphorylation of Thr498 on the β subunit markedly disables CaMKII binding.23 The relationship between CaV1.2 activating features of β subunit phosphorylation at Thr498 and the inhibitory consequences of this phosphorylation for CaMKII-β subunit binding suggest a homeostatic mechanism for limiting CaMKII-mediated increases in ICa. It will be important for future studies to determine the molecular mechanism for CaMKII binding to KV channels to better understand the physiological role of CaMKII in modulating KV channels.Is CaMKII a Multifunctional β Subunit?Ion channels exist as macromolecular protein complexes. The α subunits build the channel pore, whereas β subunits act on the pore to influence gating, expression, and assembly of α subunits. We now know that CaMKII is frequently counted among ion channel macromolecular protein complexes, raising the question of whether we should consider CaMKII to be a multifunctional ion channel β subunit. CaMKII performs a wide array of tasks that affect gating, expression, and perhaps intersubunit association.24 Thus, CaMKII is multifunctional based on its repertoire of downstream functions. CaMKII responds to catecholamines20 and angiotensin II2 and so provides an important connection between key upstream ligands, membrane excitability, and repolarization. CaMKII has "sticky fingers" that connect a wide range of ion channels to the regulatory influence of Ca2+ and reactive oxygen species.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Shawn Roach provided artistic and design assistance.Sources of FundingFunded by NIH grants R01 HL 079031, R01 HL 62494, and R01 HL 70250, the University of Iowa Research Foundation, and the Fondation Leducq Alliance for CaMKII signaling.DisclosuresM.E.A. is a named inventor on patents to treat heart disease by CaMKII inhibition.FootnotesCorrespondence to Mark E. Anderson, MD, PhD, Department of Internal Medicine, Division of Cardiovascular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail [email protected] References 1 Meyer T, Hanson PI, Stryer L, Schulman H. Calmodulin trapping by calcium-calmodulin-dependent protein kinase. 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CaM kinase augments cardiac L-type Ca2+ current: a cellular mechanism for long Q-T arrhythmias. Am J Physiol. 1999; 276: H2168–H2178.MedlineGoogle Scholar6 Dzhura I, Wu Y, Colbran RJ, Balser JR, Anderson ME. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels. Nat Cell Biol. 2000; 2: 173–177.CrossrefMedlineGoogle Scholar7 Gao L, Blair LA, Salinas GD, Needleman LA, Marshall J. Insulin-like growth factor-1 modulation of CaV1.3 calcium channels depends on Ca2+ release from IP3-sensitive stores and calcium/calmodulin kinase II phosphorylation of the alpha1 subunit EF hand. J Neurosci. 2006; 26: 6259–6268.CrossrefMedlineGoogle Scholar8 Yao J, Davies LA, Howard JD, Adney SK, Welsby PJ, Howell N, Carey RM, Colbran RJ, Barrett PQ. Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II. J Clin Invest. 2006; 116: 2403–2412.MedlineGoogle Scholar9 Couchonnal LF, Anderson ME. 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Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. Circ Res. 1999; 84: 906–912.CrossrefMedlineGoogle Scholar18 Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res. 2001; 88: 1159–1167.CrossrefMedlineGoogle Scholar19 Vinogradova TM, Maltsev VA, Bogdanov KY, Lyashkov AE, Lakatta EG. Rhythmic Ca2+ oscillations drive sinoatrial nodal cell pacemaker function to make the heart tick 17. Ann N Y Acad Sci. 2005; 1047: 138–156.CrossrefMedlineGoogle Scholar20 Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition protects against structural heart disease. 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FASEB J. 2005; 19: 1573–1575.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kepenek E, Ozcinar E, Tuncay E, Akcali K, Akar A and Turan B (2019) Differential expression of genes participating in cardiomyocyte electrophysiological remodeling via membrane ionic mechanisms and Ca2+-handling in human heart failure, Molecular and Cellular Biochemistry, 10.1007/s11010-019-03626-4, 463:1-2, (33-44), Online publication date: 1-Jan-2020. Zhang P (2017)(2017) CaMKII: The molecular villain that aggravates cardiovascular disease, Experimental and Therapeutic Medicine, 10.3892/etm.2017.4034, 13:3, (815-820), Online publication date: 1-Mar-2017. Hund T and Mohler P (2015) Role of CaMKII in cardiac arrhythmias, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2014.12.001, 25:5, (392-397), Online publication date: 1-Jul-2015. Swaminathan P, Purohit A, Hund T and Anderson M (2012) Calmodulin-Dependent Protein Kinase II: Linking Heart Failure and Arrhythmias, Circulation Research, 110:12, (1661-1677), Online publication date: 8-Jun-2012. Erickson J, He B, Grumbach I and Anderson M (2011) CaMKII in the Cardiovascular System: Sensing Redox States, Physiological Reviews, 10.1152/physrev.00018.2010, 91:3, (889-915), Online publication date: 1-Jul-2011. March 27, 2009Vol 104, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.109.195503PMID: 19325157 Originally publishedMarch 27, 2009 Keywordsion channelsCaMKIIMAGUKPDF download Advertisement
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