Regulation and targeting of central somatostatin receptors

生长抑素是神经肽信号分子家族中的一员，其功能是作为大脑中的神经递质和整个身体的激素。生长抑素的作用通常由五个特定的受体分子介导。与几乎所有神经肽受体一样，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，由生长抑素在细胞内提供，并在靶细胞部分引发一系列反应。为了完成这一功能，受体分子必须被输送到细胞表面。然而，到目前为止，只有少数研究涉及细胞如何控制单个受体类型在其表面的可用性。最近的研究表明，给定类型的受体的细胞表面输送不能被认为是理所当然的。相反，受体亚型之间存在显著的差异，例如生长抑素，因此，我建议研究生长抑素调控细胞如何控制其表面生长抑素受体的可获得性和类型。因此，它们有效地调节了它们对神经肽的敏感性，并由此延伸，对于作用于同源受体的药物。生长抑素已被证明在大脑控制脑下垂体释放激素以及微调其他神经递质和激素系统方面发挥关键作用。生长抑素系统的功能障碍经常由脑下垂体或胃肠道系统的神经内分泌肿瘤引起，并与许多疾病有关，如肢端肥大症、巨人症、阿尔茨海默病和精神分裂症。拟议中的研究将导致对生长抑素系统以及其他神经肽信号系统敏感性调节机制的更深入了解，可能为设计更有效的药物和开发新的治疗方法开辟新的道路。

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.