The proposed studies are aimed at understanding the molecular events involved in the action of inhibitory regulators of cell function from their initial interaction with target cell receptors to the final biological response of reduced secretion. The major objective of the present research plan is to investigate the mechanism by which the neuropeptide somatostatin elicits its effects in different target cells. The studies proposed will focus on the actions of somatostatin in two clonal cell lines: and endocrine cell line derived from th anterior pituitary and a neuroblastoma-derived cell strain. These cells have retained many of the differentiated functions of the tissue of origin and possess several unique properties which readily permit studies that would be difficult or impossible to interpret in other systems. Furthermore, preliminary studies indicate that the somatostatin receptor in these two cell lines are different. The following aspects of somatostatin action will be examined: 1. Mechanisms by which somatostatin regulates intracellular free Ca2+ concentrations and the importance of the induced changes in cytosolic free Ca2+ in mediating somatostatin inhibition of secretion. 2. Regulation of the binding and transduction properties of the somatostatin receptor. 3. MEchanisms by which somatostatin action is terminated. 4. Comparison of the binding properties, ligand processing capabilities and structures of somatostatin receptors in endocrine and neural target cells. A minor objective of this research plan is to examine the regulation of pituitary function by the neurotransmitter adenosine. Therefore the effects of adenosine receptor agonists and antagonists on pituitary hormone secretion will be determined in primary cultures. In addition, the intracellular mediators involved in adenosine action will be examined in the clonal pituitary cell line.
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