RGULATION OF CYCLIC GMP PHOSPHODIESTERASE BY GZ

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Much progress has been made in our understanding of how cells transmit external signals via specific cell surface receptors to internal targets. Receptor binding initiates intracellular signaling pathways, often through the activation of heterotrimeric G-proteins, eventually leading to a specific cellular response. Gz is one such heterotrimeric G-protein that exhibits unique biochemical features and limited tissue distribution. Although initial characterization of Gz has provided insight into the biochemical characterization of the protein, the downstream target(s) of Gz remain undefined. Preliminary studies utilizing the yeast two-hybrid system suggest that Gzalpha may possibly interact with the gamma subunit of cyclic GMP phosphodiesterase. G- protein regulation of phosphodiesterases has not been described outside sensory tissues, but recent identification of both Gz and phosphodiesterase gamma in various regions of the brain supports the view that this may occur. We postulate that phosphodiesterase gamma is a natural effector for Gz. Both in vitro studies and studies in intact cells will be conducted to determine whether phosphodiesterase gamma and Gzalpha associate and whether this interaction can modulate cyclic nucleotide levels by activating the phosphodiesterase complex. The proposed studies will quite possibly result in the first characterization the interaction of Gzalpha with a specific effector molecule, namely phosphodiesterase gamma.