Sensitized signalling between L-type Ca2+ channels and ryanodine   receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes

doi:10.1093/cvr/cvw247

CORC > 北京大学 > 生命科学学院

	Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes
	Zhao, Yan-Ting ; Guo, Yun-Bo ; Gu, Lei ; Fan, Xue-Xin ; Yang, Hua-Qian ; Chen, Zheng ; Zhou, Peng ; Yuan, Qi ; Ji, Guang-Ju ; Wang, Shi-Qiang
刊名	CARDIOVASCULAR RESEARCH
	2017
关键词	Excitation-contraction coupling FK506-binding protein Ryanodine receptor Calcium signalling FK506-BINDING PROTEIN FKBP12.6 RABBIT VENTRICULAR MYOCYTES RAT CARDIAC MYOCYTES HEART-FAILURE SARCOPLASMIC-RETICULUM SELECTIVE BINDING CALCIUM SPARKS LOCAL-CONTROL CONTRACTION OVEREXPRESSION
DOI	10.1093/cvr/cvw247
英文摘要	Aims The heart contraction is controlled by the Ca2+-induced Ca2+ release (CICR) between L-type Ca2+ channels and ryanodine receptors (RyRs). The FK506-binding protein FKBP12.6 binds to RyR subunits, but its role in stabilizing RyR function has been debated for long. Recent reports of high-resolution RyR structure show that the HD2 domain that binds to the SPRY2 domain of neighbouring subunit in FKBP-bound RyR1 is detached and invisible in FKBP-null RyR2. The present study was to test the consequence of FKBP12.6 absence on the in situ activation of RyR2. Methods and results Using whole-cell patch-clamp combined with confocal imaging, we applied a near threshold depolarization to activate a very small fraction of LCCs, which in turn activated RyR Ca2+ sparks stochastically. FKBP12.6-knockout and FK506/rapamycin treatments increased spark frequency and LCC-RyR coupling fidelity without altering LCC open probability. Neither FK506 nor rapamycin further altered LCC-RyR coupling fidelity in FKBP12.6-knockout cells. In loose-seal patch-clamp experiments, the LCC-RyR signalling kinetics, indexed by the delay for a LCC sparklet to trigger a RyR spark, was accelerated after FKBP12.6 knockout and FK506/rapamycin treatments. These results demonstrated that RyRs became more sensitive to Ca2+ triggers without FKBP12.6. Isoproterenol (1 mu M) further accelerated the LCC-RyR signalling in FKBP12.6-knockout cells. The synergistic sensitization of RyRs by catecholaminergic signalling and FKBP12.6 dysfunction destabilized the CICR system, leading to chaotic Ca2+ waves and ventricular arrhythmias. Conclusion: FKBP12.6 keeps the RyRs from over-sensitization, stabilizes the potentially regenerative CICR system, and thus may suppress the life-threatening arrhythmogenesis.; State Major Research and Development Program [2016YFA0500401]; National Natural Science Foundation of China [31271228, 31630035, 81370203, 81461148026, 31327901]; Project of Beijing Municipal Science and Technology Commission [Z141100000214006]; National Institutes of Health, USA [NIH R01 TW007269]; SCI(E); ARTICLE; 3; 332-342; 113
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/474830]
专题	生命科学学院
推荐引用方式 GB/T 7714	Zhao, Yan-Ting,Guo, Yun-Bo,Gu, Lei,et al. Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes[J]. CARDIOVASCULAR RESEARCH,2017.
APA	Zhao, Yan-Ting.,Guo, Yun-Bo.,Gu, Lei.,Fan, Xue-Xin.,Yang, Hua-Qian.,...&Wang, Shi-Qiang.(2017).Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes.CARDIOVASCULAR RESEARCH.
MLA	Zhao, Yan-Ting,et al."Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes".CARDIOVASCULAR RESEARCH (2017).