BIOCHEMICAL PROPERTIES OF SOMATOSTATIN RECEPTORS

生长抑素(SRIF)是生长激素的主要生理抑制剂， 胰岛素和胰升糖素的释放，因此是一种重要的调节 人类的发育、生长和新陈代谢。它还控制着神经元 大脑中的活动，并参与运动活动的调节和 啮齿动物和人类的认知。SRIF传输中的变化发生在 阿尔茨海默氏病，可能在其病理生理机制中起作用 神经精神障碍。SRIF通过以下途径诱导其生物学作用 与第二个偶联的膜结合受体相互作用 通过G蛋白的信使系统和离子通道。这样做的目的是 建议对SRIF受体的物理特性进行表征 为了更好地了解其作用的生化和细胞基础 这种重要的神经肽。我们在过去的授权期内的研究 表明受体中的碳水化合物是激动剂所必需的 结合，蛋白激酶树皮可以诱导脱敏 在体外，SRIF受体选择性地偶联到 G蛋白Gia1、Gia3和GoA。基于这些结果，我们将重点关注我们的 SRIF受体的3个主要生理方面的研究。我们会 确定受体中的碳水化合物影响的机制 高亲和力激动剂结合；SRIF受体的重要性 引起SRIF脱敏的磷酸化及其性质 SRIF受体与G蛋白的相互作用 细胞效应系统。此外，我们将继续努力 克隆SRIF受体基因。使用我们最近开发的抗体来对抗 SRIF受体，揭示SRIF受体的一级结构。这 将使我们能够识别特定的区域和氨基酸序列 参与其功能活动的受体，也将使我们能够 探讨SRIF受体结构多样性的基础 子类型。这些研究将使我们更好地了解 SRIF作用的分子基础对阐明SRIF具有重要意义 SRIF在大脑中的生理作用，对于 治疗神经精神疾病的新型治疗药物的开发 具有SRIF传播改变的疾病，如阿尔茨海默病。

Somatostatin (SRIF) is the major physiological inhibitor of growth hormone, insulin and glucagon release and therefore is an important regulator of human development, growth and metabolism. It aso controls neuronal activity in brain and is involved in the regulation of motor activity and cognition in rodents and humans. Alterations in SRIF transmission occur in Alzheimer's disease and may contribute to the pathophysiology of this neuropsychiatric disorder. SRIF induces its biological actions by interacting with membrane bound receptors which are coupled to second messenger systems and ion channels via G proteins. The objective of this proposal is to characterize the physical properties of the SRIF receptor in order to better understand the biochemical and cellular basis of action of this important neuropeptide. Our studies in the past granting period showed that carbohydrates in the receptor were essential for agonist binding, that the protein kinase BARK could induce the desensitization of the receptor in vitro and that the SRIF receptor selectively couples to the G proteins Gia1, Gia3 and Goa. Based on these results, we will focus our investigations on 3 major physical aspects of the SRIF receptor. We will identify the mechanism by which carbohydrates in the receptor influence high affinity agonist binding; the importance of SRIF receptor phosphorylation in causing SRIF desensitization and the nature of the interaction of SRIF receptors with G proteins which link the receptor to cellular effector systems. In addition, we will continue our efforts to clone SRIF receptor cDNA. using our recently developed antibody against the SRIF receptor, to reveal the primary structure of the SRIF receptor. This will allow us to identify specific regions and amino acid sequences in the receptor involved in its functional activity and will also allow us to investigate the basis for the structural diversity of SRIF receptor subtypes. These studies will provide a better understanding of the molecular basis of action of SRIF which will be important in elucidating the physiological role of SRIF in the brain and will be critical for the development of new therapeutic agents for the treatment of neuropsychiatric disorders with altered SRIF transmission such as Alzheimer's disease.