Role of G(alpha)Z in pancreatic islet beta-cell biology

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DESCRIPTION (provided by applicant): The heterotrimeric G protein, Gz, controls an unusual MAP kinase signaling cascade in neuroendocrine cells that it triggered by activation of the Ras family member, Rap1. Interestingly, one of the few places that Gz is expressed outside of the nervous system is in islet cells in the pancreas. In addition, we have recently found that a key regulator of Gz signaling, Rap1GAP, is also expressed in islet cells. Given the evidence for the importance of G protein-coupled receptors in regulation of multiple aspects of islet cell biology, this data hints at potentially very important roles for Gz in the physiology, and possible pathophysiology, of the pancreas. The experiments described in this proposal aim to develop molecular tools for dissecting the biology of Gz in the pancreatic islet cells, including the identification of reagents that directly inhibit the interaction between Gz and the Rap1 regulator Rap1GAP that we have identified, and then utilize these reagents and other experimental strategies to define the importance of the Gz/Rap1GAP interaction in signaling events important in islet cell biology.