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Study on regulatory mechanisms of gap junction conductance of cardiac muscle

心肌间隙连接电导调节机制研究

基本信息

批准号：
07670070
负责人：
IMANAGA Issei
金额：
$ 1.34万
依托单位：
Fukuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Purpose : The cardiac gap junction which is composed of channels is playing main role in cell-to-cell electrical coupling, It is generally indicated that the gap junction channels are closed by Ca^<2+> and H^+, and opened by c-AMP.It has been observed that arrhythmias due to conduction disturbances are often brought about and intracellular Ca^<2+> and H^+ ions are increased in hypoxia. In this study, infuences of hypoxia, intrabcellular Ca-overload and intracellular acidosis on gap junction electrical (longitudinal internal resistance) (ri) and conduction velocity (CV), and effectsd of c-AMP on them were examined. Results 1)By the three-compartments-chamber with shunt resistance circuit, ri and CV could simultaneously be measured on isolated multicellular cardiac tissue. 2)Time dependent increase in ri consisted with the decrease in CV induced by hypoxia. 3)c-AMP prevented and retored the deteriorated alterations of ri and CV induced by hypoxia, while it accelerated the reduction of Vmax of transmembrane action potential. 4)Increase in ri and decrease in CV induced by intracellular Ca^<2+>-overload were mitigated by lower dosis of c-AMP.5)Increse in ri and decrease in CV induced by intracellular acidosis were mitigated by c-AMP, when pH was more than 6.5.6)These effects of c-AMP were abolished by PKA inhibitor. 7)Alterations of ri and CV and effects od c-AMP on them were evidenced by morphological findings. Conclusions : It is suggested that electrical cell-to-cell uncoupling in hypoxia is due to closing effects of Ca^<2+> and H^+ ions on the gap junction channels, and c-AMP-PKA opens the closed channels or acts on the channels as up-regulation by phosphorylation of the connexin. Whether binding potency of Ca^<2+> and H^+ ions to the connexin is modified by phosphorylated state of the connexin is proposed as a novel problem.

目的：由通道组成的心脏间隙连接在细胞间电耦合中起主要作用，一般认为间隙连接通道由Ca^2+和H^+关闭，由c-AMP打开。据观察，缺氧时常因传导障碍而引起心律失常，细胞内Ca^2+和H^+离子增加。本研究探讨了缺氧、细胞内钙超载和细胞内酸中毒对间隙连接电（纵向内阻）（ri）和传导速度（CV）的影响，以及c-AMP对其的影响。结果 1)通过具有分流电阻电路的三室室，可以同时测量离体多细胞心脏组织的ri和CV。 2) ri 的时间依赖性增加与缺氧引起的 CV 减少一致。 3)c-AMP可预防和恢复缺氧引起的ri和CV的恶化变化，同时加速跨膜动作电位Vmax的降低。 4)较低剂量的c-AMP可减轻细胞内Ca^2+超载引起的ri增加和CV降低。5)当pH大于6.5.6时，c-AMP可减轻细胞内酸中毒引起的ri增加和CV降低。PKA抑制剂消除c-AMP的这些作用。 7)形态学结果证实了ri和CV的改变以及c-AMP对它们的影响。结论：缺氧时细胞间的电解偶联是由于Ca^2+和H^+离子对间隙连接通道的关闭作用所致，c-AMP-PKA打开关闭的通道或通过连接蛋白磷酸化上调作用于通道。 Ca 2+ 和H 2+ 离子与连接蛋白的结合效力是否被连接蛋白的磷酸化状态改变被提出作为一个新问题。