This is a proposal to continue studies on signaling via histamine H2 receptors in gastric parietal cells. The Principal Investigator (PI) and his colleagues have characterized the molecular structure and function of the cloned H2 receptor and determined that it activates adenylate cyclase and phospholipase C (PLC) in a GTP-dependent, cholera toxin-sensitive manner. The mechanisms whereby the receptor couples to two effector systems remain to be determined. Furthermore, the PI has recently found that the receptor mediates cell proliferation and transcriptional activation of the early response gene, c-fos. In the current proposal the following will be examined. (1) Chimeric receptor constructs and site directed mutagenesis will be used to elucidate the structural components of the receptor linked to activation of adenylate cyclase and phospholipase C; (2) the G proteins involved in H2 receptor signaling in primary and transformed cells will be characterized using selective antibodies, immunoblotting, GTP-labeling and molecular techniques; and (3) the biological significance of dual signaling will be explored. H2 receptor/G protein targeted oligopeptides, antisera and antisense probes will be used to determine the relative importance of the two signaling pathways in cell proliferation and parietal cell secretory activity.
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