Signaling Diversity Among Gqa Family Members

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Many hormones and neurotransmitters rely on the Gq class of heterotrimeric G proteins (Gq/11alpha, G14alpha, and G15/16alpha) to exert their actions at target issues. Gqalpha family members activate PLCbeta and inositol lipid signaling, and established models suggest that the cellular actions of these Galpha are identical and result from activation of Ca PKC pathways. However compelling evidence now indicated that Gq/11alpha, G14alpha, and G15/16alpha differ markedly in their overall cellular responses, their interactions with certain protein binding partners, and their cellular and biochemical properties. Contrary to established models, my working hypothesis is that Gq/11alpha, G14alpha and G15/16alpha regulate multiple overlapping and distinct signaling cascades, and are regulated differently by host cells to elicit a distinct profile of cellular responses. Consistent with this idea, Gqalph family members are expressed in different cells, and Gqalpha interacts with multiple signaling proteins besides PLCbeta, though the relative contribution of each binding partner to Gqalpha signaling is unknown. Furthermore, Gq/11alpha, G14alpha and G15/16alpha share only 57 percent overall amino acid identity, and just 12 percent identity within their first 35 residues (N- terminus) which contains fatty acids that are essential for regulating Galpha signaling capacity. Although the acylation state of G14alpha and G15/16alpha is unknown, sequence alignments predict that Gqalpha family members are modified differently. Using modem molecular, cellular, and biochemical approaches study G protein functions, the specific aims will be to: 1. Define biochemical modifications present on Gq/11alpha, G14alpha, and G15/16alpha important for regulating signaling functions. 2. Define factors that regulate Gq/11alpha, G14alpha and G15/16alpha signaling capacity including target subcelluar localization and interactions with protein binding partners. 3. Determine the diversity of cell signaling responses elicited by Gqalpha, G14alpha and G15/16alpha in selected cells, and the relative contribution of Galpha binding partners to those responses. Heterotrimeric G proteins serve essential roles in cell physiology by inking cell surface receptors to intracellular responses. G protein dysfunction is the direct cause of a growing list of human diseases, and the majority of currently available drugs exert their actions on G protein signaling pathways. These experiments will determine functional correlates for the biochemical differences observed among the Gqalpha family of G proteins, and offer new insights into the diversity and regulation of signaling responses elicited by these important G proteins. Information gained from these studies will help us to better understand G proteins as therapeutic targets.