BIOCHEMICAL PROPERTIES OF SOMATOSTATIN RECEPTORS

生长抑制素（SRIF）是生长激素的主要生理抑制剂， 因此是胰岛素和胰高血糖素释放的重要调节剂， 人类发育、生长和新陈代谢。 它阿索控制神经元 活动，参与运动活动的调节， 啮齿动物和人类的认知能力。 SRIF传输的变化发生在 阿尔茨海默病，并可能有助于这种病理生理学 神经精神障碍 SRIF通过以下方式诱导其生物学作用： 与偶联到第二受体的膜结合受体相互作用 信使系统和离子通道通过G蛋白。 的目的 建议是表征SRIF受体的物理性质， 为了更好地了解生物化学和细胞的行动基础， 这种重要的神经肽。 我们在过去的授予期内的研究 表明受体中的碳水化合物是激动剂 结合，蛋白激酶BARK可以诱导脱敏 SRIF受体选择性地偶联到受体上， G蛋白Gia 1、Gia 3和果阿。 基于这些结果，我们将专注于 研究SRIF受体的3个主要物理方面。 我们将 确定受体中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 磷酸化导致SRIF脱敏， SRIF受体与G蛋白的相互作用， 细胞效应器系统。 此外，我们会继续努力， 克隆SRIF受体cDNA。利用我们最近开发的抗体 SRIF受体，揭示SRIF受体的一级结构。 这 将使我们能够识别特定区域和氨基酸序列， 受体参与其功能活动，也将使我们能够 研究SRIF受体结构多样性的基础 亚型 这些研究将使人们更好地了解 SRIF作用的分子基础，这将是重要的阐明 SRIF在大脑中的生理作用，将是至关重要的 用于治疗神经精神疾病的新治疗剂的开发 SRIF传递改变的疾病，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.