MECHANISMS OF ACTION OF ACETYLCHOLINE IN HEART

乙酰胆碱在心脏中的作用机制

• 批准号: 3485718
• 负责人: H. CRISS HARTZELL
• 金额: $ 18.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3485718
• 关键词: Anura; acetylcholine; adenylate cyclase; calcium channel; calcium flux; cell membrane; chickens; cyclic AMP; cyclic GMP; electrophysiology; guinea pigs; heart cell; heart contraction; heart innervation; heart pharmacology; heart rhythm; hormone regulation /control mechanism; laboratory rabbit; muscarinic receptor; muscle pharmacology; muscle proteins; myocardium; neural information processing; norepinephrine; parasympathetic nervous system; phosphatidylinositols; phosphorylation; protein kinase; radiotracer; sarcolemma; sarcoplasmic reticulum; second messengers; sympathetic nervous system; tissue /cell culture

The vertebrate heart contracts spontaneously, but the force and frequency of contration are increased by norepinephrine (NE) release from sympathetic nerves and acetylcholine (ACh) released from parasympathetic nerves. These transmitters act upon several different effector systems including several different kinds of ion channels in the plasma membrane, the sarcoplasmic reticulum, and proteins in the contractile apparatus. The mechanism of action of NE is relatively well understood: NE increases contractility by stimulating adenylate cyclase which in turn activates the cAMP-dependent protein kinase that phosphorylates the appropriate effector proteins. The molecular mechanisms of action of ACh, on the other hand, are less well understood. The overall goal of this research will continue to be to elucidate the molecular mechanisms which underlie neural (particularly parasympathetic) and hormonal control of the heart. We would like to understand how the binding of ACh to receptors is transmitted to different effector systems, the nature of the "second messenger" systems invovled, and the role of each of the effector systems in regulating contraction. In this next 5-year period, we plan to focus heavily upon regulation of the trans-sarcolemmal calcium current (ICa), because this current plays a central role in determining the force of cardiac contraction. In addition, we will pursue experiments on phosphorylation of C-protein. The research will address 4 specific questions. (1) What is the mechanisms of cGMP action on ICa? We have previously shown that intracellular perfusion with cGMP decreases I Ca under certain conditions, and we have hypothesized that this decrease is mediated by a cGMP-stimulated phosphodiesterase. This hypothesis wil be tested extensively. (2) What are the mechanisms of ACh action on ICa? Does ACh act only by inhibiting adenylate cyclase, or are there other modes of ACh action? (3) Does ACh produce its positive inotropic effects on the heart by stimulating phosphoinositide metabolism and increasing ICa? (4) Are ICa and C-protein and troponin-1 phosphorylation controlled coordinately? It is hoped that these studies will provide new insights into neural control of cardiac function.

脊椎动物心自发收缩，但力量和力量 去甲肾上腺素（NE）增加了对照的频率 释放出释放的交感神经和乙酰胆碱（ACH） 来自副交感神经。 这些发射机在 几种不同的效应系统，包括几种不同的 质膜，肌质中的离子通道的种类 网状和收缩设备中的蛋白质。 这 NE的作用机理相对较充分理解：NE 通过刺激腺苷酸环化酶来提高收缩力 转动激活依赖营地的蛋白激酶 磷酸化适当的效应蛋白。 分子 另一方面，ACH的作用机制不太好 理解。 这项研究的总体目标将继续是阐明 神经基础的分子机制（尤其是 心脏的副交感神经和荷尔蒙控制。 我们会的 想了解ACH与受体的结合是如何的 传输到不同的效应器系统， “第二使者”系统被强调，并且每个系统的作用 效应系统调节收缩。 在接下来的5年期间，我们计划重点关注 反式甲钙电流（ICA）的调节， 因为这电流在确定力中起着核心作用 心脏收缩。 此外，我们将进行实验 C蛋白的磷酸化。 该研究将解决4个特定的 问题。 （1）CGMP对ICA的作用的机制是什么？ 我们先前已经表明，细胞内灌注cGMP 在某些条件下减少我的CA，我们假设 这种减少是由CGMP刺激的 磷酸二酯酶。 该假设将被广泛检验。 （2） ACH对ICA的作用机制是什么？ ACH行动 仅通过抑制腺苷酸环化酶，或者是否有其他模式 ACH行动？ （3）ACH确实会产生其阳性肌力作用 通过刺激磷酸肌醇代谢和 增加ICA？ （4）是ICA和C蛋白和肌钙蛋白-1 磷酸化协调控制？ 希望这些 研究将为心脏神经控制提供新的见解 功能。