Regulation and targeting of central somatostatin receptors

中枢生长抑素受体的调节和靶向

• 批准号: 327327-2006
• 负责人: Stroh, Thomas
• 金额: $ 2.62万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2007
• 资助国家: 加拿大
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=364305
• 关键词: Regulation; targeting; central; somatostatin; receptors

Somatostatin is a member of the neuropeptide family of signaling molecules that function as neurotransmitters in the brain and as hormones throughout the body.  The actions of somatostatin are mediated through five specific receptor molecules.  As is the case for almost all neuropeptide receptors, they belong to the large family of G protein-coupled receptors.  These receptors transmit the extracellular signal; e.g. provided by somatostatin, inside the cells and induce a cascade of reactions on the part of the target cells.  In order to fulfill this function, receptor molecules have to be delivered to the cell surface.  However, so far only a few studies have addressed how cells control the availability of individual receptor types at their surface.  Recent research has shown that cell surface delivery of a given type of receptor cannot be taken for granted.  Instead, there are marked differences between receptor subtypes, e.g. for somatostatin, in their delivery from intracellular stores to the cell surface in the absence of ligand and in the regulation of their availability at the surface by the ligand.  Therefore, I propose to investigate how cells regulated by somatostatin control the availability and types of somatostatin receptors at their surface.  Thereby, they effectively regulate their sensitivity to the neuropeptide and, by extension, to drugs acting at the cognate receptors.  Somatostatin has been shown to play a critical role in the control of hormone release from the pituitary gland by the brain and in fine tuning other neurotransmitter and hormonal systems.  Dysfunctions of the somatostatin system are frequently caused by neuroendocrine tumours of the pituitary or the gastro-intestinal system and have been implicated in a number of disorders such as acromegaly, gigantism, Alzheimer's disease and schizophrenia. The proposed studies will lead to a deeper insight into the mechanisms regulating the sensitivity of the somatostatin system and, by analogy, other neuropeptide signaling systems, potentially breaking ground for the design of more effective drugs and the development of new therapeutic approaches.

生长抑素是神经肽信号分子家族的一员，在大脑中作为神经递质发挥作用，在全身也作为激素发挥作用。生长抑素的作用是通过五种特异性受体分子介导的。与几乎所有的神经肽受体一样，它们属于G蛋白偶联受体大家族。这些受体传递细胞外信号;例如由生长激素抑制素提供，在细胞内并在靶细胞上诱导级联反应。为了实现这一功能，受体分子必须被递送到细胞表面。然而，到目前为止，只有少数研究已经阐明了细胞如何控制其表面单个受体类型的可用性。不能认为给定类型受体的表面递送是理所当然的。相反，在受体亚型之间，例如对于生长抑素，在没有配体的情况下，在它们从细胞内储存递送到细胞表面以及在配体调节它们在表面的可用性方面存在显著差异。因此，我建议研究受生长抑素调节的细胞如何控制其表面生长抑素受体的可用性和类型。因此，它们有效地调节其对神经肽的敏感性，并通过扩展，生长抑素在脑垂体释放激素的过程中起着重要的作用，并对其他神经递质和激素系统进行微调。生长抑素系统的功能障碍通常是由脑垂体或胃的神经内分泌肿瘤引起的。肠系统的损害，并与许多疾病如肢端肥大症、阿尔茨海默病、阿尔茨海默病和精神分裂症有关。拟议的研究将导致更深入地了解调节生长抑素系统敏感性的机制，并通过类比，其他神经肽信号系统，可能为设计更有效的药物和开发新的治疗方法开辟道路。