FUNCTION AND REGULATION OF SOMATOSTATIN RECEPTORS

描述：(改编自申请人的摘要)生长抑素(SS)是一种 神经肽以两种形式(SS14和SS28)存在，并作为一种激素，a 神经递质和自分泌调节剂抑制分泌和/或 内分泌、外分泌、神经细胞、免疫细胞和肿瘤细胞的增殖。党卫军有 与许多生理过程有关，包括生长、葡萄糖 动态平衡和记忆。此外，SS类似物在临床上用于 神经内分泌肿瘤的诊断和治疗，目前正在评估 治疗包括糖尿病在内的多种疾病。生物行为 通过与五个质膜受体家族的结合而启动 (sst1-sst5)通过G与效应酶和离子通道偶联。 蛋白质。每种SS受体亚型显示特定的组织和细胞 脑、垂体、内分泌和外分泌的分布模式 在胰腺和神经内分泌肿瘤中也是如此。这项提议的目标是 阐明同源和异源调控的机制 SS受体亚型。在之前的颁奖期间，我们证明了 Sst2a受体在激素结合AS后经历快速磷酸化 以及蛋白激酶C(PKC)的激活。与受体相伴 磷酸化，SS刺激sst2A受体-配体的快速内吞 这种内吞作用的速度被PKC显著地刺激 激活。相反，sst1受体的内吞作用最小。 激动剂结合。然而，sst1受体也会迅速被磷酸化。 SS处理和sst1和sst2a受体都经历了快速同源 脱敏。调查员建议检查所涉及的机制。 在sst受体脱敏、转运和再增敏中 确定同源和异源受体磷酸化在 SST受体调节。利用分子构造的生物化学分析 包括定点突变、受体缺失和嵌合体， 研究人员将确定受体磷酸化的位置并定义关键 Sst受体功能的结构域和残基。SST受体调节将是 在转基因细胞系和内源性表达细胞中进行检测 为了阐明细胞环境的作用，天然的受体 在sst受体脱敏和转运方面。

DESCRIPTION: (Adapted from the applicant's abstract) Somatostatin (SS) is a neuropeptide which exists in two forms (SS14 and SS28) and acts as a hormone, a neurotransmitter and an autocrine regulator to inhibit secretion and/or proliferation in endocrine, exocrine, neuronal, immune and tumor cells. SS has been implicated in numerous physiological processes including growth, glucose homeostasis and memory. Moreover, SS analogs are used clinically for the diagnosis and treatment of neuroendocrine tumors and are being evaluated for therapy in several diseases including diabetes mellitus. The biological actions of SS are initiated by binding to a family of five plasma membrane receptors (sst1-sst5) which are coupled to effector enzymes and ion channels via G proteins. Each SS receptor subtype shows a specific tissue and cellular distribution pattern in the brain, the pituitary, the endocrine and exocrine pancreas as well as in neuroendocrine tumors. The goal of this proposal is to elucidate the mechanisms involved in homologous and heterologous regulation of SS receptor subtypes. During the previous award period we demonstrated that the sst2A receptor undergoes rapid phosphorylation following hormone binding as well as upon activation of protein kinase C (PKC). Concomitant with receptor phosphorylation, SS stimulates rapid endocytosis of the sst2A receptor-ligand complex and the rate of this endocytosis is dramatically stimulated by PKC activation. In contrast, the sst1 receptor is minimally endocytosed upon agonist binding. However, the sst1 receptor is also rapidly phosphorylated upon SS treatment and both the sst1 and the sst2A receptors undergo rapid homologous desensitization. The investigator proposes to examine the mechanisms involved in sst receptor desensitization, trafficking, and resensitization and to determine the role of homologous and heterologous receptor phosphorylation in sst receptor regulation. Using biochemical analysis of molecular constructs which include site-specific mutants and receptor deletions and chimeras, the investigator will identify the sites of receptor phosphorylation and define key domains and residues for sst receptor function. Sst receptor regulation will be examined in both transfected cell lines and in cells endogenously expressing the native receptor in order to elucidate the role of the cellular environment in sst receptor desensitization and trafficking.