Coupling mechanisms of OP4 receptor and calcium channels

描述（由申请人提供）：本提案的长期目标是了解存在于支配心脏的大鼠交感星状神经节（SG）神经元中的阿片受体如何与参与神经递质释放的钙通道偶联。该项目将重点关注一种新发现的阿片受体（OP 4），它由伤害感受素（NOC）激活。NOC介导的OP 4受体激活通过影响自主神经系统的途径-主要是通过抑制神经传递-诱发心血管反应，如心动过缓和低血压。电生理学、分子生物学、光学和生物化学技术的结合将被用来探测Noc激活的OP 4受体调节N型钙通道的机制。该提案的具体目的是：（i）确定特定的G α亚基，耦合OP 4受体的N型钙通道;（ii）检查的动力学作用，G蛋白信号（RGS）蛋白质的调节剂在NOC介导的钙通道抑制;（iii）调查是否OP 4受体能够形成同源或异源寡聚体。OP 4受体在自主神经系统通路中发挥重要作用，有助于心率和血压调节。拟议的研究将有助于阐明这些过程的信号机制，并促进新的心血管药物的开发，用于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面积方面的确切作用。

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.