ADENOSINE A2 RECEPTORS IN BASAL GANGLIA--MECHANISM AND REGULATION

基底节腺苷A2受体——机制与调控

• 批准号: 6243757
• 负责人: J S FINK
• 金额: $ 17.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243757
• 关键词: Huntington's disease; PC12 cells; basal ganglia; brain cell; calmodulin dependent protein kinase; central neural pathway /tract; dopamine receptor; experimental brain lesion; genetic polymorphism; human tissue; immunoelectron microscopy; laboratory rat; lenticular nucleus; molecular cloning; occipital lobe /cortex; psychomotor function; purinergic receptor; receptor expression

Pharmacological evidence indicates that D2 dopaminergic (D2R) and A2a adenosinergic (A2aR) receptors interact to modulate motor function. Until recently little was known about the anatomical and cellular basis of this interaction between A2aR and D2R. We recently demonstrated that A2aR mRNA and D2R are exclusively co-expressed in a subset of rat striatal neurons which comprise the striatopallidal or "indirect" pathway of striatal efferent neurons to the major basal ganglia output nuclei. The A2aR, therefore, is located in a potentially powerful position for modulating activity in the striatopallidal pathway. No other neurotransmitter receptor has been identified which is expressed in as influential a position to selectively regulate the response of the motor system to D2R activation. The overall hypothesis of Project 3 is that interaction between A2aRs and D2Rs occurs in an subset striatal neurons and effects changes in motor behavior by regulating activity in the "indirect" striatopallidal pathway in rodents and humans. Anatomical and pharmacological evidence strongly suggests that the A2AR is of considerable importance to understanding the pathophysiology of movement disorders and the design of effective treatments. However, the cellular mechanisms by which A2aR and D2R interact to modulate motor function are not understood. Therefore, in Project 3 we propose to investigate several aspects of the biology of the A2aR particularly with reference to the human A2aR. In this Project we will characterize the (1) structure of the human A2aR gene, (2) the anatomical expression of the human A2aR gene and its protein product within the human striatum, (3) changes in activity of striatopallidal neurons in vivo resulting from interaction between A2aR and D2R, (4) the cellular mechanisms by which A2aR and D2Rs may interact to regulate activity within cells of the indirect striatal efferent pathway and (5) the mechanisms by which expression of the rat A2aR gene is regulated. These studies will provide important information about the receptor and cellular mechanisms by which A2aR and D2Rs interact to regulate motor function in human movement disorders and, possible, reveal novel approaches for regulating motor function through the "indirect" striatal efferent pathway.

药理学证据表明，D2多巴胺能（D2R）和A2a 腺苷能（A2aR）受体相互作用以调节运动功能。 直到最近，人们对人类的解剖学和细胞学基础还知之甚少。 A2aR和D2R之间的相互作用。 我们最近证明， A2aR mRNA和D2R仅在大鼠的一个亚组中共表达 纹状体神经元，包括纹状体苍白球或“间接”通路 纹状体传出神经元的主要基底节输出核。 因此，A2aR位于一个潜在的强大位置， 调节纹状体通路的活性。 没有其他 神经递质受体已被鉴定，其表达为 影响位置以选择性地调节马达的响应 系统到D2 R激活。 项目3的总体假设是， A2aRs和D2Rs之间的相互作用发生在纹状体神经元的一个子集中 并通过调节大脑中的活动来影响运动行为的变化 在啮齿类动物和人类中的“间接”纹状体苍白通路。 解剖和 药理学证据强烈表明，A2AR是一种 对理解运动的病理生理学有着相当重要的意义 疾病和设计有效的治疗方法。 然而，Cellular A2aR和D2R相互作用以调节运动功能的机制是 不理解。 因此，在项目3中，我们建议调查 A2aR生物学的几个方面，特别是参考 人类A2aR 在本项目中，我们将描述（1） 人A2aR基因的结构，（2）人A2aR基因的解剖表达， 人纹状体内的人A2aR基因及其蛋白产物，（3） 致体内纹体扁桃体神经元活性变化 A2aR和D2R之间的相互作用，（4）细胞机制， A2aR和D2R可以相互作用以调节细胞内的活性。 间接纹状体传出通路和（5）的机制， 大鼠A2aR基因的表达受到调节。 这些研究将提供 关于受体和细胞机制的重要信息， A2aR和D2R相互作用以调节人体运动中的运动功能 可能揭示了调节运动神经元的新方法， 通过“间接”纹状体传出通路发挥作用。