Muscarinic Signaling Pathways Affecting Cardiac Channels

影响心脏通道的毒蕈碱信号通路

基本信息

批准号：
6750170
负责人：
ROBERT D HARVEY
金额：
$ 26.78万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-06 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant):Parasympathetic stimulation exerts significant influence on heart rate and contractility through the release of the neurotransmitter acetylcholine, which then activates muscarinic receptors found on all cardiac myocytes. These effects are mediated in whole or in part by direct and indirect signaling mechanisms affecting cardiac ion channel activity. The indirect effects involve modulation of cAMP-dependent beta-adrenergic responses. In fact, muscarinic receptor activation inhibits as well as facilitates beta-adrenergic responses, suggesting that the net result is a balance between these inhibitory and stimulatory effects. Recent evidence suggests that in atrial preparations, both the inhibitory and stimulatory effects are mediated solely by the production of nitric oxide (NO). However, this signaling mechanism may not be as important in mediating muscarinic responses in adult ventricular myocytes. Our working hypothesis is that there is developmental regulation of the signaling pathway coupling muscarinic receptors to modulation of beta-adrenergic responses, which may lead to cell type specific signaling mechanisms in the adult heart. If this is the case, then what is responsible for muscarinic responses in adult ventricular myocytes? There is uncontested evidence that the inhibitory effects can be explained by direct G-dependent inhibition of adenylyl cyclase types V and/or VI (AC5 and AC6). However, we propose the novel idea that the stimulatory effects are due to direct G-dependent stimulation of AC4 and/or AC7. Therefore the specific aims of this proposal are to test the following four hypotheses: 1) NO does not contribute to either muscannic inhibitory or muscarinic stimulatory responses in adult ventricular myocytes; 2) muscarinic stimulatory responses in adult ventricular myocytes are due to direct G protein dependent activation of specific AC isoforms; 3) NO does contribute to muscarinic inhibitory and muscannic stimulatory signaling mechanisms in atrial myocytes; and 4) NO is also involved in muscarinic signaling mechanisms in neonatal ventricular myocytes. We will use control and genetically altered animal models to identify the signaling pathways involved in mediating muscarinic responses by recording CAMP regulated cardiac ion channel activity in conjunction with direct fluorescence measurements of cAMP activity in isolated cardiac myocytes.

描述（由申请人提供）：副交感神经刺激作用通过释放对心率和收缩力产生重大影响神经递质乙酰胆碱，然后激活毒蕈碱受体存在于所有心肌细胞中。这些影响全部或部分介导通过直接和间接信号机制影响心脏离子通道活动。间接影响涉及 cAMP 依赖性调节 β-肾上腺素能反应。事实上，毒蕈碱受体激活会抑制以及促进β-肾上腺素能反应，表明最终结果是这些抑制作用和刺激作用之间的平衡。最近的证据表明在心房准备中，抑制性和刺激性影响仅由一氧化氮（NO）的产生介导。然而，这种信号机制在介导毒蕈碱方面可能不那么重要成人心室肌细胞的反应。我们的工作假设是是信号通路耦合毒蕈碱的发育调节受体调节β-肾上腺素能反应，这可能导致细胞成人心脏中类型特定的信号传导机制。如果是这样的话，那么成人心室中毒蕈碱反应的原因是什么肌细胞？有无可争议的证据表明抑制作用可以解释为 V 型腺苷酸环化酶的直接 G 依赖性抑制和/或六（AC5 和 AC6）。然而，我们提出了一个新颖的想法，即刺激效应是由于 AC4 和/或 AC7 的直接 G 依赖性刺激所致。所以该提案的具体目的是检验以下四个假设： 1) NO 不会产生毒蕈碱抑制作用或毒蕈碱作用成人心室肌细胞的刺激反应； 2) 毒蕈碱刺激成人心室肌细胞的反应是由于直接 G 蛋白依赖性特定 AC 异构体的激活； 3) NO确实会导致毒蕈碱心房肌细胞的抑制性和麝香刺激性信号传导机制； 4) NO 还参与新生儿毒蕈碱信号传导机制心室肌细胞。我们将使用对照和基因改造的动物模型确定参与介导毒蕈碱反应的信号通路通过记录 CAMP 调节的心脏离子通道活性直接荧光测量离体心肌细胞中的 cAMP 活性。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes.

豚鼠心室肌细胞中的 cAMP 微结构域和 L 型 Ca2 通道调节。

DOI：
10.1113/jphysiol.2006.124891
发表时间：
2007
期刊：
The Journal of physiology
影响因子：
0
作者：
Warrier,Sunita;Ramamurthy,Gopalakrishnan;Eckert,RichardL;Nikolaev,ViacheslavO;Lohse,MartinJ;Harvey,RobertD
通讯作者：
Harvey,RobertD