REGULATION OF A 2-ADRENERGIC RECEPTORS/ADENYLATE CYCLASE

去甲肾上腺素和肾上腺素是重要的神经递质 在中枢神经系统和α-2肾上腺素能受体中， 与腺苷酸环化酶的抑制偶联， 分布广泛。 临床上，α-2肾上腺素能激动剂，如 可乐定和胍那苄用于治疗高血压， 其他几种疾病。 虽然可乐定被认为是 中枢控制血压，其作用机制不是 很好理解。 α-2肾上腺素能神经递质的治疗作用 激动剂通常仅在长期治疗后才明显， 这表明了适应性变化的参与。 一个更好的 了解调节和作用机制， α-2肾上腺素能受体，它们与 腺苷酸环化酶的调节对于 开发更好的药物疗法。 的总体目标 拟议的研究是了解分子基础的 细胞与α-2肾上腺素能受体 激动剂对随后的α-2肾上腺素能受体结合的影响， 腺苷酸环化酶的活性。 主要有两 效果有待研究。 第一是受体的下调 数量和脱敏的环AMP反应。 第二、 我们最近观察到α-2激动剂预处理 导致毛喉素刺激的环磷酸腺苷增加20倍 合成，我们称之为“敏化”。 对于这两组研究， 使用的模型系统是HT 29细胞系。 每个效果 将被表征，然后其分子机制 研究了 对于第一个效应，要检验的假设是 α-2肾上腺素能受体的机制 脱敏：解偶联;受体内化;和 受体丧失 我们的初步研究表明，“致敏”是 不通过cAMP介导。 因此， 已被认为具有α-2肾上腺素能受体作用，因为 以及其他第二信使系统，将进行调查。 额外的实验旨在研究可能的 腺苷酸环化酶系统的分子改变， 在致敏反应中观察到环AMP产生增加。

Norepinephrine and epinephrine are important neurotransmitters in the central nervous system, and alpha-2 adrenergic receptors, which are coupled to the inhibition of adenylate cyclase, are widely distributed. Clinically, alpha-2 adrenergic agonists such as clonidine and guanabenz are used to treat hypertension as well as several other disorders. While clonidine is thought to act centrally to control blood pressure, its mechanism of action is not well understood. The therapeutic effects of alpha-2 adrenergic agonists often are evident only after chronic treatment, suggesting the involvement of adaptive changes. Thus, a better understanding of the regulation and the mechanism of action of alpha-2 adrenergic receptors, their coupling to and their regulation of adenylate cyclase has a clear potential for the development of better drug therapies. The overall goal of the proposed research is to understand the molecular basis for the effects of preincubation of cells with an alpha-2 adrenergic agonist on subsequent alpha-2 adrenergic receptor binding and the activity of the enzyme adenylate cyclase. There are two main effects to be studied. The first is the down-regulation of receptor number and desensitization of the cyclic AMP response. Second, we have recently observed that alpha-2 agonist pretreatment results in a 20-fold increase in forskolin stimulated cyclic AMP synthesis, which we call "sensitization". For both sets of studies, the model system to be used is the HT29 cell line. Each effect will be characterized and then its molecular mechanism investigated. For the first effect, the hypothesis to be tested is that the mechanism of alpha-2 adrenergic receptor desensitization: uncoupling; receptor internalization; and receptor loss. Our initial studies indicate that "sensitization" is not mediated through cyclic AMP. Thus, other mechanisms which have been suggested for alpha-2 adrenergic receptor action, as well as other second messenger systems, will be investigated. Additional experiments are aimed at investigating the possible molecular alterations in the adenylate cyclase system which cause the increased cyclic AMP production seen with sensitization.