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绝大多数突触传播由神经递质使者介导。传播信息取决于刺激从受体转移到细胞内效应子。腺苷酸环化酶的激素刺激活动是一种受体效应耦合的模型系统广泛研究。但是，直到最近，关注的关注程度要少得多针对激素抑制腺苷酸环化酶和相关的圭烷核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），也可能有一个单独的亚基调节激动剂的结合。在完整人血小板的一系列研究，我们发现了调节 alpha2激动剂的结合在功能上与这些激动剂产生的腺苷酸环化酶的抑制作用。另外，最大抑制腺苷酸环化酶在低水平上发生 α2-肾上腺素受体的占用率。这个发现让人想起在刺激系统中的研究，我们获得了直接证据的证据我们系统中存在备用受体。在目前的赠款中时期，我希望进一步描述药理学和确定以下双性化手段：（1）子群是否容易在没有鸟甘核苷酸的情况下相连；（2）哪个亚群（S）与抑制腺苷酸环化酶有关。这这些研究的发现可能与其他受体系统有关与腺酸环化酶成反比。另外，备用受体理论的同时计算机模拟将提供研究完整受体储备的理论指南血小板；反过来，实验研究将提供经验模拟指南。我们最近的临床调查实验室以及其他人都检查了α2肾上腺素能受体在血小板中作为主要抑郁症的生物标记。这该提案中描述的研究将增加我们对血小板中的α2受体，将有助于复杂而新颖使用血小板α2受体作为生物标记的方法神经精神病的临床研究。