Grant: Operating Grant

G protein-coupled receptors (GPCRs) represent the largest class of cell surface receptor molecules and are the targets of most drugs used in the therapy of metabolic and neurological disorders. They transmit extracellular signals, e.g. provided by endogenous signalling molecules or by medical drugs, inside the cells and induce a cascade of reactions on the part of the target cells. In order to fulfil this function, receptor molecules have to be delivered to the cell surface. Sst1, sst2, and sst5 are members of a family of GPCRs mediating the effects of somatostatin (SST), a member of the neuropeptide family of signalling molecules. There are marked differences between these receptor subtypes in their delivery from intracellular stores to the cell surface but only a few studies have addressed how cells control the availability of individual GPCR types at their surface membrane. Therefore, I propose to investigate how SST-responsive cells control the availability of SST receptor subtypes at the cell surface. Thereby, they effectively regulate their sensitivity to SST and, by extension, to drugs acting at the same receptors. SST plays 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 SST 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 major depression. The proposed studies will provide a deeper insight into the mechanisms regulating the sensitivity of the SST receptor family and, by analogy, other GPCR signalling systems. They will also demonstrate the roles of gender and endogenous rhythms (e.g. hormonal rhythms) in the regulation of cell surface receptors and potentially break ground for the design of more effective drugs and new therapeutic approaches.