PLATELET ALPHA 2 RECEPTORS--MODELS FOR EFFECTOR COUPLING

血小板 ALPHA 2 受体——效应器耦合模型

基本信息

批准号：
3449712
负责人：
JOHN ELLIS
金额：
$ 5.21万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-04-01 至 1987-09-30
项目状态：
已结题

项目摘要

The vast majority of synaptic transmission in the mammalian nervous system is mediated by neurotransmitter messengers. Propagation of this information depends upon the transfer of the stimulus from the receptor to intracellular effectors. The hormonal stimulation of adenylate cyclase activity is a model system of receptor-effector coupling that has been studied extensively. Until recently, however, much less attention has been directed toward hormonal inhibition of adenylate cyclase and the related effects of guanyl nucleotides on the receptor binding of agonists. Recent studies in many laboratories have suggested that separate regulatory subunits mediate the stimulatory and inhibitory hormonal regulation of adenylate cyclase (Ns and Ni respectively) and that there may also be a separate subunit for the regulation of the binding of agonists. In a series of studies in intact human platelets, we have found the regulation of the binding of alpha2 agonists to be functionally dissociated from the inhibition of adenylate cyclase that is produced by these agonists. Additionally, maximal inhibition of adenylate cyclase occurs at low levels of occupancy of alpha2-adrenergic receptors. This finding is reminiscent of studies in stimulatory systems, and we have obtained direct evidence for the presence of spare receptors in our system. In the present grant period, I expect to further characterize the agonist-subpopulations of alpha2 adrenergic receptors of intact platelets by pharmacological and bichemical means to determine: (1) whether the subpopulations are readily interconverted in the absence of guanyl nucleotides; and (2) which subpopulation(s) is related to the inhibition of adenylate cyclase. The findings from these studies may have relevance to other receptor systems which are inversely coupled to adenyate cyclase. Additionally, a concurrent computer-simulation of spare receptor theory will provide theoretical guidelines to the study of the receptor reserve of intact platelets; in turn, the experimental study will provide empirical guidelines for the simulation. Recent clinical investigations in our laboratory, as well as others, have examined the alpha2 adrenergic receptor in the platelet as a biological marker in major depressive disorders. The studies described in this proposal will increase our understanding of alpha2 receptors in the platelet and will contribute to complex and novel approaches to the use of platelet alpha2 receptors as biological markers in clinical studies of neuropsychiatric disease.

哺乳动物神经系统中的绝大多数突触传递由神经递质信使介导。传播此信息取决于刺激从受体到受体的传递细胞内效应器。腺苷酸环化酶的激素刺激活性是受体-效应器耦合的模型系统，已被广泛研究。然而直到最近，人们对针对腺苷酸环化酶和相关的激素抑制鸟苷酸对激动剂受体结合的影响。最近的许多实验室的研究表明，单独的监管亚基介导刺激性和抑制性激素调节腺苷酸环化酶（分别为 Ns 和 Ni），并且可能还存在用于调节激动剂结合的单独亚基。在一个在完整的人类血小板中进行了一系列研究，我们发现了调节 α2激动剂的结合从功能上解离抑制这些激动剂产生的腺苷酸环化酶。此外，腺苷酸环化酶的最大抑制发生在低水平 α2-肾上腺素能受体的占据。这个发现让人回想起刺激系统的研究，我们已经获得了直接证据我们的系统中存在备用受体。在目前的补助金中在此期间，我希望进一步描述激动剂亚群的特征完整血小板的α2肾上腺素受体的药理学和生化方法可确定： (1) 亚群是否易于在没有鸟苷酸的情况下相互转化；和 (2) 其中亚群与腺苷酸环化酶的抑制有关。这这些研究的结果可能与其他受体系统相关其与腺苷酸环化酶反向偶联。另外，一个备用受体理论的并行计算机模拟将提供完整受体储备研究的理论指导血小板；反过来，实验研究将提供实证模拟指南。我们最近的临床研究实验室以及其他人已经检查了α2肾上腺素受体血小板中作为重度抑郁症的生物标志物。这本提案中描述的研究将增加我们对血小板中的α2受体将有助于复杂和新颖的使用血小板α2受体作为生物标志物的方法神经精神疾病的临床研究。