MOLECULAR CHARACTERIZATION OF H2 RECEPTOR DUAL SIGNALING

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DESCRIPTION (adapted from investigator's abstract and/or aims): This is a resubmission of an application to study the molecular mechanisms and biological significance of histamine H2 receptor coupling to both cAMP and calcium signaling pathways. Coupling of the H2 receptor to the cAMP pathway is well established; however, histamine H2-receptor associated elevation of intracellular calcium is more recent, having been first observed in rabbit parietal cells in 1986. This observation has now been confirmed in several species including dog and similar data published for HL60 cells.In the parietal cell, numerous studies have demonstrated a clear association between the cAMP pathway and increased HCl secretion; however, the physiological relevance of histamine coupling to the calcium signaling pathway in parietal cells has not been established. Following the recent cloning of the H2 receptor in 1991, the applicant in collaboration with Dr. Yamada and colleagues demonstrated that stable transfection of the H2 receptor into HEPA cells resulted in H2 receptor coupling to adenyl cyclase/cAMP and phospholipase C/calcium/inositol triphosphate (IP3) signaling pathways. The specific aims of this proposal are to continue this line of investigation as follows: 1) To characterize the structural components of the H2 receptor that are linked to the two pathways using chimeric H2 receptors in concert with receptor based synthetic peptides; 2) To characterize the G-proteins involved in dual signaling pathways in both primary and transformed cells; 3) On the basis of knowledge gained from the first two specific aims, to utilize H2 receptor/G-protein-targeted oligopeptides, antisera and antisense probes to determine the relative importance of the dual signaling mechanism in parietal cell secretory activity. Since H2 receptor activation also modulates a number of biologically diverse responses in different cell types, an understanding of its function is expected to have broad biological significance.