G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization
G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization
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DOI：
10.1093/cvr/cvt240
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发表时间：
2014-01-01
影响因子：
10.8
通讯作者：
Jespersen, Thomas
中科院分区：
文献类型：
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作者：
Liang, Bo;Nissen, Jakob D.;Jespersen, Thomas
本研究的目的是探讨g蛋白偶联内向整流钾（GIRK）通道在心室中的功能作用。免疫荧光实验表明，在GIRK1敲除（KO）小鼠中，GIRK4定位于外肌肉瘤和t小管中，而在GIRK4 KO小鼠中未检测到GIRK4标记。GIRK4定位于大鼠脑室间插椎间盘，而在大鼠心房间插椎间盘和外肌柱中表达。GIRK4定位于人室性心内膜和心外膜的t小管和间盘，但在心肌中部缺失。离体大鼠心室组织电生理记录显示，腺苷A(1)受体激动剂n6 -环戊基ladenosine （CPA）和乙酰胆碱（ACh）可缩短动作电位持续时间（APD），而APD的缩短可被GIRK通道阻滞剂tertiapin-Q、腺苷A(1)受体拮抗剂DPCPX或毒毒碱M-2受体拮抗剂AF-DX 116逆转。在没有外源受体激活的情况下，terapin - q延长了APD。此外，CPA和ACh均可缩短有效不应期，而terapin - q、DPCPX或AF-DX 116均可逆转这一作用。受体激活也会使静息膜电位超极化，这一效应被terapin - q逆转。相反，在没有外源受体激活的情况下，terapin - q会使静息膜电位去极化。共聚焦显微镜显示，在不同的物种中，GIRK4在心室中有不同的定位，并且在人的心室壁中有异质表达。电生理记录显示，GIRK电流可能显著促进心室复极，从而影响心脏电稳定性。
The purpose of this study was to investigate the functional role of G-protein-coupled inward rectifier potassium (GIRK) channels in the cardiac ventricle.Immunofluorescence experiments demonstrated that GIRK4 was localized in outer sarcolemmas and t-tubules in GIRK1 knockout (KO) mice, whereas GIRK4 labelling was not detected in GIRK4 KO mice. GIRK4 was localized in intercalated discs in rat ventricle, whereas it was expressed in intercalated discs and outer sarcolemmas in rat atrium. GIRK4 was localized in t-tubules and intercalated discs in human ventricular endocardium and epicardium, but absent in mid-myocardium. Electrophysiological recordings in rat ventricular tissue ex vivo showed that the adenosine A(1) receptor agonist N6-cyclopentyladenosine (CPA) and acetylcholine (ACh) shortened action potential duration (APD), and that the APD shortening was reversed by either the GIRK channel blocker tertiapin-Q, the adenosine A(1) receptor antagonist DPCPX or by the muscarinic M-2 receptor antagonist AF-DX 116. Tertiapin-Q prolonged APD in the absence of the exogenous receptor activation. Furthermore, CPA and ACh decreased the effective refractory period and the effect was reversed by either tertiapin-Q, DPCPX or AF-DX 116. Receptor activation also hyperpolarized the resting membrane potential, an effect that was reversed by tertiapin-Q. In contrast, tertiapin-Q depolarized the resting membrane potential in the absence of the exogenous receptor activation.Confocal microscopy shows that among species GIRK4 is differentially localized in the cardiac ventricle, and that it is heterogeneously expressed across human ventricular wall. Electrophysiological recordings reveal that GIRK current may contribute significantly to ventricular repolarization and thereby to cardiac electrical stability.