Spontaneous inward currents reflecting oscillatory activation of Na+/Ca2+ exchangers in human embryonic stem cell-derived cardiomyocytes

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• 作者：Seong Woo Choi ; Hyang-Ae Lee ; Sung-Hwan Moon…
• 关键词：Embryonic stem cell ; Heart ; Pacemaker current ; NCX ; Ca2+ release
• 刊名：Pfl¨¹gers Archiv - European Journal of Physiology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：468
• 期：4
• 页码：609-622
• 全文大小：2,319 KB
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• 作者单位：Seong Woo Choi (1)
  Hyang-Ae Lee (1) (3)
  Sung-Hwan Moon (4)
  Soon-Jung Park (4)
  Hae Jin Kim (1) (2)
  Ki-Suk Kim (1) (3)
  Yin Hua Zhang (1) (2)
  Jae Boum Youm (5)
  Sung Joon Kim (1) (2)
  
  1. Department of Physiology, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
  3. Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Daejeon, Republic of Korea
  4. Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Republic of Korea
  2. Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea
  5. Department of Physiology, College of Medicine, Inje University, Busan, Republic of Korea
  
• 刊物主题：Human Physiology;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-2013

文摘

Na+/Ca2+ exchanger current (I_NCX) triggered by spontaneous Ca2+ release from sarcoplasmic reticulum (SR) has been suggested as one of the cardiac pacemaker mechanisms (“Ca2+ clock model”). In human embryonic stem cell-derived cardiomyocytes (hESC-CMs) showing spontaneous action potentials (APs), we found that substantial population (35 %) showed regular oscillation of inward currents (SICs) in nystatin-perforated voltage clamp between −40 and 40 mV (−80 ± 10.6 pA, at −20 mV). SICs were similarly observed between nodal, atrial, and ventricular hESC-CMs. Oscillations of [Ca2+]_i synchronized with SICs were observed under voltage clamp. SICs were eliminated by lowering [Ca2+]_e, L-type Ca2+ channel (VOCC_L) blocker (nifedipine, 10 µM), ryanodine receptor (RyR) agonist (caffeine, 10 mM), or NCX inhibitor (1 µM SN-6 and 10 µM KB-R7943). Plasma membrane expression of NCX1 was confirmed using immunofluorescence confocal microcopy. Both caffeine and SN-6 slowed the pacemaker potential but did not abolish the AP generation. The inhibitors of funny current (3 µM ivabradine) or voltage-gated K+ channel currents (1 µM E4031 and 10 µM chromanol-293B) also did not abolish but slowed the pacemaker potential. In a computational model of cardiac pacemaker by Maltsev and Lakatta (2009), after modifying the spatial distribution of RyR, VOCC_L, and NCX by using our multiparameter adjust algorithm, we could successfully reproduce spontaneous SR Ca2+ release and SICs under voltage clamp. It was proposed that, under the membrane depolarization activating VOCC_L, oscillatory Ca2+ releases via RyR induce sharp increases in subsarcolemmal [Ca2+]_i and inward I_NCX (SICs). Since the hESC-CMs without SICs still showed spontaneous APs, the putative “Ca2+ clock” would provide a redundant pacemaker or augmenting mechanism in hESC-CMs.