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1.

001-es BibID:BIBFORM057406
Első szerző:Magyar János (élettanász)
Cím:Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias / János Magyar, Tamás Bányász, Norbert Szentandrássy, Kornél Kistamás, Péter P. Nánási, Jonathan Satin
Dátum:2015
ISSN:1381-6128
Megjegyzések:The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling. Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR. Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Heart
gap junction
beat-to-beat variability
arrhythmia
Megjelenés:Current Pharmaceutical Design. - 21 : 8 (2015), p. 1042-1052. -
További szerzők:Bányász Tamás (1960-) (élettanász) Szentandrássy Norbert (1976-) (élettanász) Kistamás Kornél (1986-) (biológus) Nánási Péter Pál (1956-) (élettanász) Satin, Jonathan
Pályázati támogatás:K109736
OTKA
K100151
OTKA
PD101171
OTKA
K101196
OTKA
NK104331
OTKA
TÁMOP-4.2.4.A/2-11/1-2012-0001
TÁMOP
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2.

001-es BibID:BIBFORM037325
Első szerző:Magyar János (élettanász)
Cím:Rem-GTPase regulates cardiac myocyte L-type calcium current / Magyar J., Kiper C. E., Sievert G., Cai W., Shi G. X., Crump S. M., Li L., Niederer S., Smith N., Andres D. A., Satin J.
Dátum:2012
Megjegyzések:Rationale: The L-type calcium channels (LTCC) are critical for maintaining Ca ( 2+) -homeostasis. In heterologous expression studies, the RGK-class of Ras-related G-proteins regulates LTCC function; however, the physiological relevance of RGK-LTCC interactions is untested. Objective: In this report we test the hypothesis that the RGK protein, Rem, modulates native Ca ( 2+) current (ICa,L) via LTCC in murine cardiomyocytes. Methods and Results: Rem knockout mice (Rem (-/-) ) were engineered, and ICa,L and Ca ( 2+) -handling properties were assessed. Rem (-/-) ventricular cardiomyocytes displayed increased ICa,L density. ICa,L activation was shifted positive on the voltage axis, and β-adrenergic stimulation normalized this shift compared with wild-type ICa,L. Current kinetics, steady-state inactivation, and facilitation was unaffected by Rem (-/-) . Cell shortening was not significantly different. Increased ICa,L density in the absence of frank phenotypic differences motivated us to explore putative compensatory mechanisms. Despite the larger ICa,L density, Rem (-/-) cardiomyocyte Ca ( 2+) twitch transient amplitude was significantly less than that compared with wild type. Computer simulations and immunoblot analysis suggests that relative dephosphorylation of Rem (-/-) LTCC can account for the paradoxical decrease of Ca ( 2+) transients. Conclusions: This is the first demonstration that loss of an RGK protein influences ICa,L in vivo in cardiac myocytes.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
monomer G-protein
heart
calcium channel
Megjelenés:Channels 6 : 3 (2012), p. 166-173. -
További szerzők:Kiper, Carmen E. Sievert, Gail Cai, Weikang Shi, Geng-Xian Crump, Shawn M. Li, Liren Niederer, Steven Smith, Nic Andres, Douglas Satin, Jonathan
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3.

001-es BibID:BIBFORM032928
035-os BibID:WOS:000225354300015
Első szerző:Magyar János (élettanász)
Cím:Divergent action potential morphologies reveal nonequilibrium properties of human cardiac Na channels / János Magyar, Carmen E. Kiper, Robert Dumaine, Don E. Burgess, Tamás Bányász, Jonathan Satin
Dátum:2004
ISSN:0008-6363
Megjegyzések:Objective: Fast inward Na current (INa) carried by the voltage-gated Na channel (NaV1.5) is critical for action potential (AP) propagation and the rapid upstroke of the cardiac AP. In addition, a small fraction of NaV1.5 channels remains open throughout the plateau of the AP, and this current is termed as late INa. In patients with mutant NaV1.5-based congenital long Q?T (LQT) syndrome, mutant channels pass more late INa compared to wild-type channels in unaffected patients. Although LQT mutant NaV1.5 channels are well studied, there is no careful evaluation of the effects of cardiac APs on early and late current. This is important with the recent documentation of nonequilibrium INa.Methods: We measured AP-stimulated INa through NaV1.5 wild-type and two LQT mutant channels (?KPQ and N1325S). Three distinct AP morphologies were used: human embryonic stem cell-derived cardiac myocyte (hES-CM) APs with a relatively slow upstroke and canine endocardial and epicardial ventricular myocytes with rapid upstrokes.Results: All three APs elicited both early and late INa. For wild-type NaV1.5, the hES-CM AP elicits more early and late INa than either the endocardial or epicardial AP. The mechanism for this difference is that the hES-CM has a relative slow dV/dtmax that causes a maximal open channel probability. Slower upstroke stimulation also allows greater Na flux through wild-type and N1325S channels, but not the ?KPQ mutant.Conclusions: The inherent gating properties of NaV1.5 provide natural tuning of optimal INa density. Slower upstroke velocities can yield more INa and Na flux in some NaV1.5 variants.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Cardiovascular Research. - 64 : 3 (2004), p. 477-487. -
További szerzők:Kiper, Carmen E. Dumaine, Robert Burgess, Don E. Bányász Tamás (1960-) (élettanász) Satin, Jonathan
Pályázati támogatás:OTKA-T043182
OTKA
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DOI
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4.

001-es BibID:BIBFORM020232
035-os BibID:WOS:000294414700010
Első szerző:Magyar János (élettanász)
Cím:Long term regulation of cardiac L-type calcium channel by small G proteins / Magyar J., Jenes A., Kistamas K., Ruzsnavszky F., Nanasi P. P., Satin J., Szentandrassy N., Banyasz T.
Dátum:2011
ISSN:0929-8673
Megjegyzések:Calcium ions are crucial elements of excitation-contraction coupling in cardiac myocytes. The intracellular Ca(2+) concentration changes continously during the cardiac cycle, but the Ca(2+) entering to the cell serves as an intracellular second messenger, as well. The Ca(2+) as a second messenger influences the activity of many intracellular signalling pathways and regulates gene expression. In cardiac myocytes the major pathway for Ca(2+) entry into cells is L-type calcium channel (LTCC). The precise control of LTCC function is essential for maintaining the calcium homeostasis of cardiac myocytes. Dysregulation of LTCC may result in different diseases like cardiac hypertrophy, arrhytmias, heart failure. The physiological and pathological structural changes in the heart are induced in part by small G proteins. These proteins are involved in wide spectrum of cell biological functions including protein transport, regulation of cell proliferation, migration, apoptosis, and cytoskeletal rearrangement. Understanding the crosstalk between small G proteins and LTCC may help to understand the pathomechanism of different cardiac diseases and to develop a new generation of genetically-encoded Ca(2+) channel inhibitors.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Molekuláris Medicina
Megjelenés:Current Medicinal Chemistry. - 18 : 24 (2011), p. 3714-3719. -
További szerzők:Jenes Ágnes (1980-) (élettanász) Kistamás Kornél (1986-) (biológus) Ruzsnavszky Ferenc (1984-) (élettanász) Nánási Péter Pál (1956-) (élettanász) Satin, Jonathan Szentandrássy Norbert (1976-) (élettanász) Bányász Tamás (1960-) (élettanász)
Pályázati támogatás:TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
A feszültségfüggő K-csatornák szerepe excitábilis sejtekben
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5.

001-es BibID:BIBFORM051687
035-os BibID:(WOS)000330177900028
Első szerző:Manning, Janet R.
Cím:Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction / Janet R. Manning, Guo Yin, Catherine N. Kaminski, Janos Magyar, Han-Zhong Feng, John Penn, Gail Sievert, Katherine Thompson, J.-P. Jin, Douglas A. Andres, Jonathan Satin
Dátum:2013
Megjegyzések:Background-?The small GTPase Rad is a negative regulator of voltage-dependent L-type calcium channel current (ICaL); however,the effects of Rad ablation on cardiomyocyte function are unknown. The objective of this study is to test the hypothesis that Raddepletioncauses positive inotropic effects without inducing cardiac hypertrophy.Methods and Results-?Ventricular myocytes from adult Rad / mice were isolated and evaluated by patch-clamp recordings for ICa,L and action potentials, Ca2+ transients, and sarcomere shortening. Maximum ICaL is elevated in Rad / (maximal conductance 0.35 0.04 picoSiemens/picoFarad (pS/pF) wild-type; 0.61 0.14 pS/pF Rad / ), decay kinetics are faster, and ICa,L activates at lower voltages (activation midpoint 7.2 0.6 wild-type; 11.7 0.9 Rad / ) mimicking effects of beta-adrenergic receptor stimulation. Diastolic and twitch calcium are elevated in Rad / (F340/380: 1.03 diastolic and 0.35 twitch for wild-type; 1.47diastolic and 0.736 twitch for Rad / ) and sarcomere shortening is enhanced (4.31% wild-type; 14.13% Rad / ) at lower pacing frequencies. Consequentially, frequency-dependence of Ca2+ transients is less in Rad / , and the frequency dependence of relaxation is also blunted. In isolated working hearts, similar results were obtained; chiefly, +dP/dt was elevated at baseline and developed pressure was relatively nonresponsive to acute adrenergic receptor stimulation. In single cells, at subphysiologicalfrequencies, nonstimulated calmodulin-dependent protein kinase?sensitive calcium release is observed. Remarkably, Rad / hearts did not show hypertrophic growth despite elevated levels of diastolic calcium.Conclusions-?This study demonstrates that the depletion of Rad GTPase is equivalent to sympathomimetic b-adrenergic receptor, without stimulating cardiac hypertrophy. Thus, targeting Rad GTPase is a novel potential therapeutic target for Ca2+-homeostasis?driven positive inotropic support of the heart.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
L-type calcium current
Rad
RGK
beta-adrenergic stimulation
Megjelenés:Journal of American Heart Association. - 2 : 6 (2013), p. e000459. -
További szerzők:Yin, Guo Kaminski, Catherine N. Magyar János (1961-) (élettanász) Feng, Han-Zhong Penn, John Sievert, Gail Thompson, Katherine Jin, J.-P. Andres, Douglas Satin, Jonathan
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DOI
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6.

001-es BibID:BIBFORM032929
Első szerző:Satin, Jonathan
Cím:Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes / Jonathan Satin, Izhak Kehat, Oren Caspi, Irit Huber, Gil Arbel, Ilanit Itzhaki, Janos Magyar, Elizabeth A. Schroder, Ido Perlman, Lior Gepstein
Dátum:2004
ISSN:0022-3751
Megjegyzések:Human embryonic stem cell-derived cardiomyocytes (hES-CMs) are thought to recapitulate the embryonic development of heart cells. Given the exciting potential of hES-CMs as replacement tissue in diseased hearts, we investigated the pharmacological sensitivity and ionic current of mid-stage hES-CMs (20?35 days post plating). A high-resolution microelectrode array was used to assess conduction in multicellular preparations of hES-CMs in spontaneously contracting embryoid bodies (EBs). TTX (10 ?m) dramatically slowed conduction velocity from 5.1 to 3.2 cm s?1 while 100 ?m TTX caused complete cessation of spontaneous electrical activity in all EBs studied. In contrast, the Ca2+ channel blockers nifedipine or diltiazem (1 ?m) had a negligible effect on conduction. These results suggested a prominent Na+ channel current, and therefore we patch-clamped isolated cells to record Na+ current and action potentials (APs). We found for isolated hES-CMs a prominent Na+ current (244 ? 42 pA pF?1 at 0 mV; n = 19), and a hyperpolarization-activated current (HCN), but no inward rectifier K+ current. In cell clusters, 3 ?m TTX induced longer AP interpulse intervals and 10 ?m TTX caused cessation of spontaneous APs. In contrast nifedipine (Ca2+ channel block) and 2 mm Cs+ (HCN complete block) induced shorter AP interpulse intervals. In single cells, APs stimulated by current pulses had a maximum upstroke velocity (dV/dtmax) of 118 ? 14 V s?1 in control conditions; in contrast, partial block of Na+ current significantly reduced stimulated dV/dtmax (38 ? 15 V s?1). RT-PCR revealed NaV1.5, CaV1.2, and HCN-2 expression but we could not detect Kir2.1. We conclude that hES-CMs at mid-range development express prominent Na+ current. The absence of background K+ current creates conditions for spontaneous activity that is sensitive to TTX in the same range of partial block of NaV1.5; thus, the NaV1.5 Na+ channel is important for initiating spontaneous excitability in hES-derived heart cells.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Journal of Physiology (London) 559 : 2 (2004), p. 479-496. -
További szerzők:Kehat, Izhak Caspi, Oren Huber, Irit Arbel, Gil Itzhaki, Ilanit Magyar János (1961-) (élettanász) Schroder, Elizabeth Perlman, Ido Gepstein, Lior
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7.

001-es BibID:BIBFORM032937
035-os BibID:PMID:17158651
Első szerző:Schroder, Elizabeth
Cím:Chronic verapamil treatment remodels ICa,L in mouse ventricle / Elizabeth Schroder, Janos Magyar, Don Burgess, Douglas Andres, Jonathan Satin
Dátum:2007
ISSN:0363-6135
Megjegyzések:In this study we tested the hypothesis that ventricular homeostasis of L-type Ca(2+) current (I(Ca,L)) minimally involves regulation of the main pore-forming alpha-subunit (Ca(V)1.2) and auxiliary proteins that serve as positive or negative regulators of I(Ca,L). We treated animals for 24 h with verapamil (Ver, 3.6 mg.kg(-1).day(-1)), isoproterenol (Iso, 30 mg.kg(-1).day(-1)), or Iso + Ver via osmotic minipumps. To test for alterations of Ca(2+) channel complex components we performed real-time PCR and Western blot analysis on ventricle. In addition, cardiac myocytes (CMs) were dispersed and current was recorded in the whole cell configuration to evaluate I(Ca,L). Surprisingly, 24- to 48-h Ver increased Ca(V)1.2 mRNA and protein and I(Ca,L) current (Ver 11 +/- 1pA/pF vs. control 7 +/- 0.5pA/pF; P < 0.01). I(Ca,L) from CMs in Ver mice showed no change in whole cell capacitance. To examine the in vivo effects of a physiologically relevant Ca(2+) channel agonist, we treated mice with Iso. Twenty-four-hour Iso infusion increased heart rate; Ca(V)1.2- and Ca(V)beta(2) mRNA levels were constant, but the Ca(2+) channel subunit mRNA Rem was increased twofold. Cells isolated from 24-h Iso hearts showed no change in basal I(Ca,L) density and diminished responsiveness to acute 1 muM Iso. To further examine the homeostatic regulation of the Ca(2+) channel, we treated animals for 24 h with Iso + Ver. The influence of Iso + Ver was similar that of to Iso alone on Ca(2+) channel mRNAs and I(Ca,L), with the exception that it prevented the increase in Rem seen with Iso treatment. Long-term Ca(2+) channel blockade induces an increase of Ca(V)1.2 mRNA and protein and significantly increases I(Ca,L).
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:American Journal of Physiology-Heart And Circulatory Physiology 292 : 4 (2007), p. H1906-H1916. -
További szerzők:Magyar János (1961-) (élettanász) Burgess, Don E. Andres, Douglas Satin, Jonathan
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