Electropharmacological analysis of the signal transduction mechanisms of the delayd rectifier potassium channel of heart cells.

心脏细胞延迟整流钾通道信号转导机制的电药理学分析

• 批准号: 03454141
• 负责人: IIJIMA Toshihiko
• 金额: $ 3.78万
• 依托单位: Akita University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03454141/
• 关键词: Ventricular cells; Patch-clamp method; Adenylate cyclase; Forskolin derivative; Delayd rectifier K^+ current; L-type Ca^<2+> current; Aortic endothelial cell; intracellular Ca^<2+>; 単離心室筋細胞; 細胞内情報伝達機構; L型カルシウムイオンチャンネル; 遅延整流カリウムイオンチャンネル; フォルスコリ

This study was designed to investigate the differential modulation of the L-type Ca^<2+> (I_<Ca>) and the delayd rectifier K^+ current (I_K) by direct activation of adenylate cyclase in guinea pig ventricular cells. Isoproterenol equally and simultaneously increased both I_<Ca> and I_K in a same threshold concentration, but a water soluble forskolin derivative, NKH477, increased I_K at lower threshold concentrations than that for increasing I_<Ca>. Selective stimulation of beta-1 adrenoceptors, on the other hand, elicited an increase in I_<Ca> more sensitively than I_K. These results suggest that a simple signal transduction pathway from beta adrenoceptors to I_<Ca> and I_K channels mediated through adenylate cyclase and cyclic AMP-dependent protein kinase is not sufficient to explain these differences. It is, therefore, concluded that I_<Ca> and I_K channels could be differentially regulated during beta adrenoceptor stimulation.Mechanisms responsible for the sustained elevation in intracellular free Ca^<2+> concentration ([Ca^<2+>]_i) in response to histamine and ATP were also studied in cultured human aortic endothelial cells loaded with the fluorescent Ca^<2+> indicator fura-2. Results indicate that the sustained elevation of [Ca^<2+>]_i is resulted from the Cl^--sensitive entry of extracellular Ca^<2+> in human aortic endothelial cells.

本研究旨在探讨直接激活腺苷酸环化酶对豚鼠心室细胞l型Ca^<2+> (I_<Ca>)和延迟整流K^+电流（I_K）的差异调节。异丙肾上腺素在相同的阈值浓度下，同时增加I_K和I_<Ca>，但水溶性福斯柯林衍生物NKH477在较低的阈值浓度下增加I_K，而不是增加I_<Ca>。另一方面，β -1肾上腺素受体的选择性刺激比I_K更敏感地引起I_<Ca>的增加。这些结果表明，通过腺苷酸环化酶和环amp依赖性蛋白激酶介导的从β -肾上腺素受体到I_<Ca>和I_K通道的简单信号转导途径不足以解释这些差异。因此，我们认为I_<Ca>和I_K通道在β肾上腺素受体刺激过程中可能受到不同程度的调节。我们还在培养的人主动脉内皮细胞中研究了负载荧光Ca^<2+>指示物fura-2的细胞内游离Ca^<2+>浓度（[Ca^<2+>]_i）响应组胺和ATP持续升高的机制。结果表明，[Ca^<2+>]_i持续升高是由于细胞外Ca^<2+>对Cl^-敏感进入人主动脉内皮细胞所致。

项目成果

E.Hosoki&T.Iijima: "Chloride-sensitive Ca^<2+> entry by histamine and ATP in human aortic endothelial cells." Eur.J.Pharmacol.(Mol.Pharmacol.Sec.). 266. 213-218 (1994)

细木

K.Harada and T.Iijima: "Differential modulation by adenylate cyclase of Ca2^+ and delayed K^+ current in ventricular myocytes."

K.Harada 和 T.Iijima：“腺苷酸环化酶对心室肌细胞中 Ca2^ 的差异调节和延迟的 K^ 电流。”

Hosoki,E.: "Chloride-sensitive Ca^<2+> entry by histamine and ATP in human aortic endothelial cells." European Journal of Pharmacoloqy(Molecular pharmacoloqy Section). 266. 213-218 (1994)

Hosoki,E.：“人主动脉内皮细胞中组胺和 ATP 对氯化物敏感的 Ca^2 进入”。

K.Harada & T.Iijima: "Differential modulation by adenylate cyclase of Ca^<2+> and delayd K^+ current in ventricular myocytes." Am.J.Physiol. in press. (1994)

原田健

T.Iijima,M.Hosono and N.Taira: "Electropharmacological analysis of the forskolin binding site on adenylate cyclase in single ventricular cells of the guinea-pig heart."

T.Iijima、M.Hosono 和 N.Taira：“豚鼠心脏单心室细胞中腺苷酸环化酶上毛喉素结合位点的电药理学分析。”