FUNCTIONAL PROPERTIES OF BRAIN SOMATOSTATIN RECEPTORS

描述(改编自申请人的摘要)：SRIF是一个 中枢神经递质参与运动活动的控制 和认知功能。SRIF在调节认知功能中的作用 对阿尔茨海默病有重要的临床意义 (AD)，一种与SRIF水平降低相关的神经精神障碍 边缘结构和严重的认知障碍。由于SRIF受体 AD大脑中的水平是正常的，SRIF替代疗法可能对 治疗这种疾病。SRIF通过相互作用诱导其生物学作用 与细胞表面相关的受体。最近的克隆研究已经 确定了五种SRIF受体亚型，称为SSTR1-5。这个 本提案的目标是确定以下各项的具体功能 大脑中的单个SRIF受体亚型。在上一时期内 在支持下，申请者在SSTR2、3和4开发了选择性激动剂。 这些激动剂将在本项目中用于识别特定的 受体亚型的功能。这些多肽将被碘化，然后 放射性配基将被用来定位大脑中这些 受体亚型被表达，并可能介导SRIF的选择性作用。 研究人员产生的抗血清可以与 SSTR2，他们正在开发针对其他受体亚型的抗血清 它将用于进一步本地化CNS中表达这些 通过免疫印迹和免疫细胞化学检测受体。去调查 这些受体亚型的选择性细胞功能，它们具有稳定的 在PC12细胞中表达每个受体，以确定受体是否 利用全细胞偶联钙离子通道和钾离子通道 膜片钳电生理技术。此外，子类型 申请者开发的选择性激动剂将用于 确定在脑神经元中表达的SSTR2-4是否与这些离子偶联 电导通道。亚型选择性激动剂将在 确定哪些受体介导刺激的行为研究 SRIF对运动活动和认知功能的影响。这个 SRIF多肽的认知效应将通过被动回避进行评估 行为和八臂径向迷宫。该项目还将测试 非肽类SRIF类似物可通过以下途径进入大脑 外周给药逆转认知的能力 药物耗尽中枢SRIF对啮齿动物的损伤作用 半胱胺。此项目更广泛的相关性是确定 SRIF受体亚型在脑内的特殊功能 开发用于治疗的SRIF药物的潜在基础 涉及SRIF传递失衡的中枢神经系统疾病，如阿尔茨海默病。

DESCRIPTION (Adapted from applicant's abstract): SRIF is a neurotransmitter in the CNS involved in the control of locomotor activity and cognitive functions. The role of SRIF in mediating cognitive functions has important clinical implications with regards to Alzheimer's disease (AD), a neuropsychiatric disorder associated with diminished SRIF levels in limbic structures and severe cognitive impairments. Since SRIF receptor levels are normal in AD brain, SRIF replacement therapy could be useful in treating this disorder. SRIF induces its biological actions by interacting with cell surface associated receptors. Recent cloning studies have identified five SRIF receptor subtypes referred to as SSTR1-5. The objective of this proposal is to identify the specific functions of these individual SRIF receptor subtypes in the brain. During the previous period of support, the applicants developed selective agonists at SSTR2,3 and 4. These agonists will be used in the present project to identify specific functions of the receptor subtypes. The peptides will be iodinated and the radioligands will be employed to localize sites in the brain where these receptors subtypes are expressed and may mediate selective actions of SRIF. The investigators have generated antisera that specifically interacts with SSTR2, and they are developing antisera against the other receptor subtypes which will be used to further localize sites in the CNS expressing these receptors by immunoblotting and immunocytochemistry. To investigate selective cellular functions of these receptor subtypes, they have stably expressed each receptor in PC12 cells to determine whether the receptors couple to calcium (Ca2+) and potassium (K+) ion channels using whole-cell patch clamp electrophysiological techniques. Furthermore, the subtype selective agonists, which the applicants have developed, will be used to determine whether SSTR2-4 expressed in brain neurons couple to these ionic conductance channels. The subtype selective agonists will be tested in behavioral studies to determine which receptors mediate the stimulatory effects of SRIF on locomotor activity and cognitive functions. The cognitive effects of SRIF peptides will be assessed using passive avoidance behaviors and the eight-arm radial maze. The project will also test non-peptidic SRIF analogs that can gain entrance to the brain following peripheral administration for their ability to reverse cognitive impairments in rodents induced by depleting central SRIF with the drug cysteamine. The broader relevance of this project is to identify the specific functions of SRIF receptor subtypes in brain to provide a potential foundation for developing SRIF drugs to be used in the treatment of CNS disorders involving imbalances in SRIF transmission, such as AD.