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Protein kinase C-mediated regulation of the electrical activity in cardiac pacemaker cells (1995)

蛋白激酶 C 介导的心脏起搏细胞电活动调节 (1995)

基本信息

批准号：
06670738
负责人：
HABUCHI Yoshizumi
金额：
$ 0.32万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Possible contribution of protein kinase C (PKC) to the cardiac pacemaker activity was investigated using sinoatrial and atrioventricular node cells isolated from rabbits. The membrane currents and action potentials were measured with the patch clamp method. In order to activate the PKC, angiotensin II, endothelin and a phorbol ester TPA were tised. Angiotensin II and endothelin significantly reduced the L-type Ca current I_<Ca> in sinoatrial node cells, and reduced the spontaneous firing rate. This inhibition of the I_<Ca> was inhibited by a protein kinase A inhibitor or dialysis of the cells with extrinsic cAMP. A pretreatment with pertussis toxin also abolished the effects of angiotensin II and endothelin. The angiotensin II-induced inhibition of I_<Ca> was dose-dependent, however at higher concentrations (【greater than or equal】30 nM), the initial inhibition was followed by a graduai increase in the I_<Ca>. TPA, a protein kinase activator, gradually increased the I_<Ca> by approxima … More tely 15%. This time course resembled the gradual increase in I_<Ca> observed with high concentrations of angiotensin II. The pretreatment with TPA did not reduce the effects of angiotensin II and endothelin. Acetylcholine also inhibited the I_<Ca> in these pacemaking cells, and angiotensin II did not show any additional effect to acetylcholine. According to these results, it is concluded that activation of protein kinase C enhances I_<Ca>, which can cause a positive chronotropic effect. However, the receptors which are coupled with the phospholipase C-protein kinase pathway are also linked with the pertussis toxin-sensitive G_i-adenylate cyclase pathway. Thus, application of these vasoactive peptides reduces the heart rate by lowering the intracellular cAMP concentration. This negative chronotropic effect is attenuated with time presumably through the desensitization of the receptor and PKC-induced potentiation of I_<Ca>. Long-term effects of PKC on the ion channels remain to be resolved. Less

用离体兔窦房结细胞和房室结细胞研究了蛋白激酶C（PKC）对心脏起搏活动的可能作用。用膜片钳法测定细胞膜电流和动作电位。为了激活PKC，血管紧张素II，内皮素和佛波酯TPA被激活。血管紧张素II和内皮素可显著降低窦房结细胞L-型钙电流I_1<Ca>，降低自发放电频率。这种抑制作用<Ca>可被蛋白激酶A抑制剂或用外源性cAMP透析细胞所抑制。百日咳毒素预处理也消除了血管紧张素II和内皮素的作用。血管紧张素II诱导的I_2的抑制<Ca>是剂量依赖性的，然而在较高浓度（[大于或等于]30 nM）下，初始抑制之后是I_2的逐渐增加<Ca>。TPA是一种蛋白激酶激活剂，随着时间的推移<Ca>， ...更多信息 15%。该时间过程类似于<Ca>在高浓度血管紧张素II下观察到的I_2的逐渐增加。TPA预处理不能降低血管紧张素II和内皮素的作用。乙酰胆碱也抑制这些起搏细胞的I_2<Ca>，而血管紧张素II对乙酰胆碱没有任何附加作用。根据这些结果，可以得出结论，蛋白激酶C的激活增强I_<Ca>，这可以引起正性变时效应。然而，与磷脂酶C-蛋白激酶途径偶联的受体也与百日咳毒素敏感的G_i-腺苷酸环化酶途径相关联。因此，这些血管活性肽的应用通过降低细胞内cAMP浓度来降低心率。这种负性变时效应随着时间的推移而减弱，可能是通过受体的脱敏和PKC诱导的I_的增强<Ca>。PKC对离子通道的长期影响仍有待解决。少