Coupling mechanisms of NOP receptors and calcium channels

描述(申请人提供)：拟议研究的长期目标是进一步了解参与疼痛信号的大鼠星状神经节(SG)神经元中阿片受体1(NOP，或OP4)阿片受体对N型钙通道的调制。本项目将集中于鉴定导致NOP受体脱敏的特定信号转导元件、结构性活性受体的药理学特征和N型钙通道抑制。NOP受体被内源性多肽Niciceptin FQ(N/OFQ)激活。N/OFQ激活的NOP受体可在动物疼痛模型中发挥镇痛或镇痛作用。临床研究表明，SG阻滞剂可用于治疗患有慢性面部疼痛或头痛的患者。将结合电生理学、免疫荧光和分子技术来探讨NOP受体调节N型钙通道的机制。这项建议的具体目的是：i)确定介导N/OFQ刺激的N型钙通道抑制的特异性Gb和GG亚基；ii)确定介导NOP受体脱敏的G蛋白偶联受体激酶(GRK)亚型；iii)确定GRK和Gb蛋白与固有活性的NOP受体的相互作用，并研究这些受体的药理学特征。已知NOP受体和N型钙通道参与痛觉传递。因此，拟议的研究将有助于阐明这些过程背后的信号机制，并有助于开发治疗疼痛的新药物，如与慢性头痛和复杂区域疼痛综合征相关的药物，同时防止阿片类药物耐受和成瘾。与公共健康相关：这项拨款提案的目的是研究参与疼痛过程的阿片受体调节钙离子进入神经的细胞机制。我们将确定影响这些受体功能反应的特定细胞蛋白，我们还将研究这些受体的药理学。这些研究将带来新的信息，这些信息可以用来帮助治疗疼痛，而不会产生耐受性或阿片成瘾。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to further our understanding of N-type Ca2+ channel modulation by opioid receptor-like 1 (NOP, or OP4) opioid receptors in rat stellate ganglion (SG) neurons involved in pain signaling. This project will focus on identifying the specific signal transduction elements that contribute to NOP receptor desensitization, the pharmacological profile of constitutively active receptors and N-type Ca2+ channel inhibition. The NOP receptor is activated by the endogenous peptide nociceptin FQ (N/OFQ). N/OFQ-activated NOP receptors can exert algesic or analgesic effects in animal pain models. Clinical studies have shown that SG blockade can be used to treat patients that suffer from chronic facial pain or headaches. A combination of electrophysiological, immunofluorescence, and molecular techniques will be used to probe the mechanisms by which NOP receptors modulate N-type Ca2+ channels. The specific aims of this proposal are to: i) identify the specific Gb and Gg subunits that mediate N-type Ca2+ channel inhibition for N/OFQ-stimulated ii) identify the G protein-coupled receptor kinase (GRK) isoform that mediates desensitization of NOP receptors iii) to determine the interaction of GRK and Gb proteins with constitutively active NOP receptors, as well as to examine the pharmacological profile of the receptors. NOP receptors and N-type Ca2+ channels are known to participate in pain transmission. Thus, the proposed studies will help to clarify the signaling mechanisms underlying these processes and aid in the development of novel agents for the treatment of pain, such as those associated with chronic headache and complex region pain syndrome, and at the same time prevent opioid tolerance and addiction. PUBLIC HEALTH RELEVANCE: The purpose of this grant proposal is to examine the cellular mechanisms by which opiate receptors that are involved in pain processes regulate the entry of Ca2+ ions into nerves. We will identify specific cellular proteins that affect the functional response of these receptors, and we will also study the pharmacology of these receptors. These studies will lead to new information that can be employed to help treat pain without developing tolerance or opiate addiction.