FUNCTION AND REGULATION OF SOMATOSTATIN RECEPTORS

生长抑素受体的功能和调节

• 批准号: 6198385
• 负责人: AGNES SCHONBRUNN
• 金额: $ 28.91万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198385
• 关键词: cell line; fluorescence microscopy; hormone receptor; hormone regulation /control mechanism; immunofluorescence technique; laboratory rabbit; neuropeptide receptor; peptide hormone analog; phosphorylation; protein isoforms; protein kinase C; protein structure function; receptor binding; receptor coupling; receptor expression; receptor mediated endocytosis; receptor sensitivity; somatostatin; transfection

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.

描述：（改编自申请人的摘要）生长抑素（SS）是一种 神经肽以两种形式存在（SS14 和 SS28），充当激素、 神经递质和自分泌调节剂以抑制分泌和/或 内分泌、外分泌、神经元、免疫和肿瘤细胞的增殖。党卫军有 参与许多生理过程，包括生长、葡萄糖 体内平衡和记忆。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，并正在评估 治疗包括糖尿病在内的多种疾病。生物作用 SS 是通过与五个质膜受体家族结合而启动的 (sst1-sst5) 通过 G 与效应酶和离子通道偶联 蛋白质。每个 SS 受体亚型都显示出特定的组织和细胞 大脑、垂体、内分泌和外分泌的分布模式 胰腺以及神经内分泌肿瘤。该提案的目标是 阐明参与同源和异源调节的机制 SS受体亚型。在上一个奖项期间，我们证明了 sst2A 受体在激素结合后经历快速磷酸化 以及蛋白激酶 C (PKC) 的激活。与受体同时存在 磷酸化，SS 刺激 sst2A 受体-配体的快速内吞作用 复合体，并且这种内吞作用的速率受到 PKC 的显着刺激 激活。相反，sst1 受体被最小程度地内吞 激动剂结合。然而，sst1 受体也会快速磷酸化。 SS 处理后 sst1 和 sst2A 受体均发生快速同源 脱敏。研究者建议检查所涉及的机制 SST 受体脱敏、贩运和再敏化以及 确定同源和异源受体磷酸化的作用 sst受体调节。使用分子结构的生化分析 其中包括位点特异性突变体、受体缺失和嵌合体， 研究人员将确定受体磷酸化的位点并确定关键 sst受体功能的结构域和残基。 Sst受体调节将是 在转染细胞系和内源表达细胞中进行检查 天然受体以阐明细胞环境的作用 SST 受体脱敏和贩运。