A variety of hormone signaling pathways rely on the interaction of three proteins: receptors, which are responsible for recognizing and discriminating between a multitude of extracellular signals; effectors, which are enzymes or ion channels that produce changes in intracellular messengers, such as cAMP, cGMP, and Ca2+; and heterotrimeric G proteins, which mediate communication between receptors and effectors. With the recent identification of several hundred receptors and effectors, the major interest of the laboratory is to understand how the G proteins mediate communication in a specific fashion. The G proteins are composed of two functional units: the a (alpha) subunit and the bg (beta-gamma) subunit complex that functions as a single entity. Through recent advances in molecular and protein chemistry, dual roles for the bg subunits have been revealed in the upstream recognition of receptors and in the downstream regulation of effectors. Consistent with these roles, there are now known to be six b subunits and twelve g subunits. In particular, the g subunits show a high degree of structural diversity that is likely to translate into functional heterogeneity. Although in vitro assays have provided invaluable information on possible combinations of b and g subunits, it is not known whether such combinations of b and g subunits actually exist in the physiological setting and whether they contribute to the specificity of hormone signaling between and within cells of the body. Thus, the goal of this competing research proposal is to focus on potential mechanisms by which the b g subunits contribute to the fidelity of hormone signaling. To achieve this goal, the plan is to: 1) continue to explore the structural diversity of the g subunits through the identification and characterization of new subunits; 2) examine the role of the g subunits in the oligomeric organization of G proteins of physiologic significance; 3) determine the role, and study the underlying basis, for selective interactions between the bg subunits and receptors through the use of in vitro approaches; 4) elucidate the physiological functions of specific bg subunits in particular hormone receptor signaling pathways through the use of in vivo approaches; and 5) begin to define factors controlling the functions of the bg subunits. The knowledge gained by elucidating the biochemical activities and physiological functions of the G protein bg subunits may expand the understanding of how hormone signals are discriminated and faithfully transmitted from a particular receptor across the membrane to the appropriate effector.
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