STRUCTURAL ANALYSIS OF THE ALPHA 2 ADRENERGIC RECEPTOR

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DESCRIPTION (Applicant's Abstract) A long term objective of this research effort is to define factors that influence the specificity and efficiency of signal propagation by receptors (R) coupled to heterotrimeric G-proteins (G). A major determinant of signalling specificity/efficiency for G-protein coupled receptors is the cell specific expression of the subtypes of the primary signalling entities, R, G and effector (E). Another major site for regulating signalling specificity/efficiency lies at the R-G or G-E interface where these interactions are influenced by cell architecture, stoichiometry and accessory proteins that regulate signal transfer from R to G or G to E. This application focuses on the identification and characterization of a candidate "accessory protein(s)" that is a novel and powerful activator of G-proteins. The applicants have recently achieved partial purification of the protein, termed the G-protein activator, from the neuroblastoma-glioma cell hybrid NG108-15. The immediate goals of this application are to functionally characterize and determine the primary sequence of the G-protein activator. The SPECIFIC AIMS are: 1) Characterize the interaction of the G-protein activator with G-proteins; 2) Functional characterization of the G-protein activator relative to signal transduction events; 3) Determine the primary sequence of the G-protein activator. The G-protein activator and related molecules may regulated the activation of G-proteins independent of receptors or perhaps regulated receptor signalling via their ability to influence signal intensity and/or duration of specific transduction pathways. Molecules of this class may regulate the signal amplification commonly observed with signalling events involving G-proteins and may be of particular significance in tissues requiring rapid signal processing or under conditions of aberrant cell growth and development. The demonstration of proteins that influence signal propagation downstream from receptor at the level of G-protein presents a new frontier for understanding disease processes and developing novel therapeutics that either mimic or interfere with their actions.