REGULATION OF ION CHANNELS IN VASCULAR SMOOTH MUSCLE

血管平滑肌离子通道的调节

• 批准号: 3357833
• 负责人: NICHOLAS SPERELAKIS
• 金额: $ 16.98万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3357833
• 关键词: G protein; angiotensin II; calcium channel; cardiovascular pharmacology; electrophysiology; guinea pigs; hypertension; laboratory rat; neurotransmitters; phosphatidylinositols; phosphorylation; potassium channel; tissue /cell culture; vascular smooth muscle; vasoactive agent; vasomotion

The ion channels in the membrane of vascular smooth muscle cells play an important role in excitation-contraction coupling and in setting vasomotor tone. The activity of these ion channels is controlled by neurotransmitters such as norepinephrine, vasoactive hormones such as angiotensin-II, an clinically useful drugs such as Ca2+ antagonists. The ion channels may be regulated either directly or indirectly by these substances, and the regulatory processes may include the formation or release of intracellular messengers, such as Ca2+, ATP, G-proteins, cyclic AMP, cyclic GMP, inositol phosphates (IP3/IP4), and diacylglycerol. In some disease states, the properties and/or regulation of the ion channels may be altered. Since blood vessels from different regions have different degrees of excitability,k the proportion of various ion channels and/or their regulatory processes may differ also. The objective of this study is to investigate in detail the specific characteristics and regulatory mechanisms for the ion channels, including the various types of Ca2+ and K+ channels, in freshly isolated and cultured vascular smooth muscle cells. Macroscopic and microscopic (single-channel) currents will be recorded using whole-cell voltage clamp and patch-clamp techniques, respectively. The influence of intracellular levels of Ca2+, ATP, and cyclic nucleoties on the activity of Ca2+ and K+ channels will be determined by intracellular perfusion of these substances. A possible role of phosphorylation mediated by various protein kinases (i.e., cyclic nucleotide-dependent, Ca2+/calmodulin-dependent, and Ca2+/phospholipid-dependent) in regulating ion channel activity and cellular excitability will be explored. The mechanism of action of vasoactive substances will be investigated. The possible role of phosphoinositide metabolism (i.e., IP3, IP4, and diacyclglycerol formation) in the electrophysiological actions of agonists such as angiotensin-II will be assessed. The possible gating of ion channels by G-proteins will also be investigated. The results of these studies should provide comprehensive information about how ion channels in vascular smooth muscle function and are regulated and should help to clarify how cellular excitability is altered by important vasoactive substances.

血管平滑肌细胞膜中的离子通道发挥 在激发反应耦合和设置血管舒缩剂中的重要作用 语气。 这些离子通道的活性由 神经递质，例如去甲肾上腺素，血管活性激素，例如 血管紧张素II，一种临床上有用的药物，例如Ca2+拮抗剂。 这 离子通道可以直接或间接地受到这些通道的调节 物质，监管过程可能包括形成或 释放细胞内信使，例如Ca2+，ATP，G蛋白，环状 AMP，环状GMP，肌醇磷酸盐（IP3/IP4）和二酰基甘油。 在 一些疾病状态，离子通道的特性和/或调节 可能会改变。 由于来自不同地区的血管有不同 兴奋性程度，k各种离子通道和/或的比例 他们的监管过程也可能有所不同。 这项研究的目的是 详细研究特定特征和调节 离子通道的机制，包括各种类型的Ca2+和K+ 通道，新鲜分离和培养的血管平滑肌细胞。 将记录宏观和微观（单通道）电流 分别使用全电池电压夹和斑块钳技术。 细胞内Ca2+，ATP和环状核的影响 关于Ca2+和K+通道的活性将由细胞内确定 这些物质的灌注。 磷酸化介导的可能作用 通过各种蛋白激酶（即循环核苷酸依赖性， Ca2+/钙调蛋白依赖性，而Ca2+/磷脂依赖性）在调节中 将探索离子通道活性和细胞兴奋性。 这 将研究血管活性物质的作用机理。 这 磷酸肌醇代谢的可能作用（即IP3，IP4和 激动剂的电生理作用 例如血管紧张素-II将进行评估。 离子的门控 G蛋白的渠道也将进行研究。 这些结果 研究应提供有关离子渠道如何中的全面信息 血管平滑肌功能并受到调节，应有助于 澄清重要血管活性如何改变细胞兴奋性 物质。