G-Protein Coupled Receptor Oligomerization in the CNS

CNS 中的 G 蛋白偶联受体寡聚化

• 批准号: 6702686
• 负责人: LAURA S STONE
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702686
• 关键词: G protein; MDCK cell; afferent nerve; alpha adrenergic receptor; analgesia; biological signal transduction; central nervous system; drug tolerance; immunoprecipitation; laboratory rat; ligands; mass spectrometry; opioid receptor; protein structure function; receptor binding; receptor coupling; substance P; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): It is now recognized that co-localized opioid, adrenergic and other GPCRs may be associated as dimers and oligomers in addition to the traditionally envisaged monomeric species. These developments have resulted in considerable re-evaluation of our models of GPCR structure and function. Although many reports of GPCR oligomerization now exist, the vast majority of studies have been conducted in transfected cells in vitro. In fact, there are very few reports investigating the existence of GPCR heteromers in vivo. The significance and role of oligomerization in GPCR function in CNS tissue therefore remains largely unexplored. Agonists acting at spinal delta-opioid and alpha-2A-adrenergic receptors inhibit pain transmission and interact synergistically when co-administered in the spinal cord and are highly co-localized in primary afferent neurons (an obvious prerequisite for oligomerization). We propose to utilize these receptor subtypes as a physiologically relevant model to explore the functional implications and importance of GPCR oligomerization in the CNS. We propose a series of studies designed to directly identify heteromeric species in CNS tissue. In addition, we will explore the nature of these interaction(s) at the molecular and cellular levels to identify a potential role for GPCR heteromerization in analgesic synergy. Improving our understanding of the existence of and functional implications of oligomerization in opioid receptor biology could lead to insights into the cellular and molecular mechanisms of analgesic synergy, tolerance and dependency. These studies could therefore have a significant impact in future drug discovery and treatment approaches to narcotic addiction and the treatment of severe acute and chronic pain.

描述（由申请人提供）：现在认识到，除了传统设想的单体物质外，共定位的阿片类、肾上腺素能和其他GPCR可能以二聚体和寡聚体形式相关。这些发展导致了对我们的GPCR结构和功能模型的大量重新评估。虽然现在存在许多GPCR寡聚化的报道，但绝大多数研究都是在体外转染细胞中进行的。事实上，很少有研究体内GPCR异聚体存在的报道。因此，在CNS组织中GPCR功能中寡聚化的意义和作用在很大程度上仍然未被探索。 作用于脊髓δ-阿片受体和α-2A-肾上腺素能受体的激动剂抑制疼痛传递，当在脊髓中共同给药时协同相互作用，并且在初级传入神经元中高度共定位（寡聚化的明显先决条件）。我们建议利用这些受体亚型作为生理相关的模型，以探讨功能的影响和GPCR寡聚化在中枢神经系统中的重要性。我们提出了一系列的研究，旨在直接确定在中枢神经系统组织中的异聚体物种。此外，我们将在分子和细胞水平上探索这些相互作用的性质，以确定GPCR异聚化在镇痛协同作用中的潜在作用。 提高我们对阿片受体生物学中寡聚化的存在和功能影响的理解，可以深入了解镇痛协同作用，耐受性和依赖性的细胞和分子机制。因此，这些研究可能会对未来的药物发现和治疗方法产生重大影响，以麻醉剂成瘾和治疗严重的急性和慢性疼痛。