Gonadotropin releasing hormone (GnRH) is an endocrine substance that regulates pituitary gonadotropes by binding and activation of a specific plasma membrane receptor. Occupancy of the receptor by GnRH or by one of its agonists, leads to mobilization of extracellular calcium to an intracellular locus. Mobilization of calcium is regulated by a receptor-activated calcium ion channel which shows similar, but not identical, sensitivity to inhibitors of calcium channels identified in other systems. In addition, the receptor is coupled, by a GTP binding protein (""""""""G protein""""""""), to the metabolism of phosphatidylinositol (PI) leading to the producing of measurable increases of diacylglycerols (DAGs) and inositol phosphates (IPs). Evidence exists for roles of calmodulin (activated by calcium mobilized in response to GnRH) and protein kinase C (activated by calcium and DA); these calcium binding proteins may serve as intermediates in message transduction in response to GnRH. Both of these redistribute from the cytosol to the plasma membrane in vivo as an early and specific action of GnRH and agents that activate calmodulin and protein kinase C also provoke gonadotropin release in a synergistic fashion. During the past nine years our laboratory has characterized the rat pituitary model and shown it to be a representative system for study of the action of this neuroendocrine peptide. The proposed studies will center around a detailed examination of the receptor- effector system involved in transducing the signal from GnRH. This system regulates gonadotropin release, regulation of cellular responsiveness, and receptor numbers. We now have available assays that will enable us to assess changes in receptor numbers an ligand affinity in addition to size changes, the functional state of the calcium ion channel, receptor-effector coupling and involvement of calcium, lipids, and calcium binding proteins. The functional interactions of these molecules will be examined in order to enhance the resolution of our understanding of the molecular basis of GnRH action. The work proposed should afford us the opportunity to precisely define the molecular basis of receptor- effector coupling, resulting in advances in our understanding of hormone action. This area is significant as it forms the basis of our understanding of the clinical and veterinary utility of GnRH.
Showing the most recent 10 out of 160 publications
