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（由申请人提供）：该提案的长期目标是了解将心脏支配的大鼠交感神经神经节（SG）神经元中存在的阿片类药物受体如何与涉及神经递质释放的钙通道有关。该项目将集中于新鉴定的阿片类受体（OP4），该受体被NociTeptin（NOC）激活。 NOC介导的OP4受体激活引起心血管反应，例如心动过缓和通过影响自主神经系统的途径 - 通过抑制神经传播。将使用Etectrophyolyolyoly，分子，光学和生化技术的组合来探测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）确定将OP4受体与N型钙通道相结合的特定Galpha亚基； （ii）检查了G蛋白信号传导（RGS）蛋白在NOC介导的钙通道抑制中起作用的动力学作用； （iii）研究OP4受体是否能够形成同型或异弱者。 OP4受体在有助于心率和血压调节的自主神经系统途径中起重要作用。拟议的研究将有助于阐明这些过程的信号传导机制，并促进新型心血管剂的发展，以治疗同情性张力增加而导致的高血压。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降低心肌梗死大小方面的确切作用。