Coupling mechanisms of OP4 receptor and calcium channels

OP4受体与钙通道的偶联机制

• 批准号: 6793227
• 负责人: Victor Ruiz-Velasco
• 金额: $ 26.2万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793227
• 关键词: G protein; biological signal transduction; calcium channel; dimer; electrophysiology; fluorescence resonance energy transfer; heart function; immunoprecipitation; laboratory rat; neural transmission; neurons; nociceptin; opioid receptor; protein protein interaction; protein structure; protein structure function; receptor coupling; sympathetic ganglion; voltage /patch clamp

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how opioid receptors, present in rat sympathetic stellate ganglion (SG) neurons innervating the heart, couple to calcium channels involved in neurotransmitter release. This project will focus on a newly identified opioid receptor (OP4) that is activated by nociceptin (NOC). Noc-mediated OP4 receptor activation elicits cardiovascular responses such as bradycardia and hypotension via pathways that influence the autonomic nervous system--mostly through an inhibition of neural transmission. A combination of etectrophysiological, molecular, optical and biochemical techniques will be used to probe the mechanisms whereby Noc-activated OP4 receptors modulate N-type calcium channels. The specific aims of the proposal are to: (i) identify the specific Galpha subunit that couples OP4 receptors to N-type calcium channels; (ii) examine the kinetic role which regulators of G protein signaling (RGS) proteins play in Noc-mediated calcium channel inhibition; (iii) investigate whether OP4 receptors are capable of forming homo- or hetero-oligomers. OP4 receptors play an important role in the autonomic nervous system pathways that contribute to heart rate and blood pressure regulation. The proposed studies will help to clarify the signaling mechanisms underlying these processes and facilitate the development of novel cardiovascular agents for treating hypertension resulting from increased sympathetic tone. Moreover, the information gathered from these studies may help determine the precise role opioids play in decreasing myocardial infarct size.

描述(申请人提供)：这项建议的长期目标是了解存在于支配心脏的交感星状神经节(SG)神经元中的阿片受体是如何与参与神经递质释放的钙通道耦合的。该项目将专注于一种新发现的阿片受体(OP4)，该受体由伤害素(NOC)激活。NOC介导的OP4受体激活通过影响自主神经系统的途径引起心血管反应，如心动过缓和低血压--主要是通过抑制神经传递。将结合电生理、分子、光学和生化技术来探索Noc激活的OP4受体调节N型钙通道的机制。该提案的具体目的是：(I)确定OP4受体与N型钙通道偶联的特定Galpha亚基；(Ii)研究G蛋白信号转导蛋白(RGS)的调节蛋白在Noc介导的钙通道抑制中所起的动力学作用；(Iii)研究OP4受体是否能够形成同种或异种寡聚体。OP4受体在自主神经系统调节心率和血压的通路中起着重要作用。建议的研究将有助于阐明这些过程背后的信号机制，并促进开发新的心血管药物来治疗交感神经张力增加引起的高血压。此外，从这些研究中收集的信息可能有助于确定阿片类药物在减少心肌梗死范围方面所起的确切作用。