Regulation and targeting of central somatostatin receptors

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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.