G Protein Beta-Gamma and Beta-RGS Dimers--Structure /Fun

Diabetes, Digestive, Kidney Diseases

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Abstract

G-proteins, or guanine-nucleotide binding regulatory proteins, are heterotrimers which function as transmembrane signal transducers by coupling receptors for extracellular stimuli to intracellular effectors (enzymes, ion channels). G-proteins constitute a diverse family distinguished by specific receptor and effector interactions which in turn are determined by the structure of the three constituent subunits. The alpha subunit binds guanine nucleotides and has a well-established role in effector modulation. The beta and gamma subunits are tightly associated as a beta-gamma complex, comprising a single functional entity which, like the alpha subunit, is absolutely required for G protein interaction with receptor. An effector-regulatory role for the beta-gamma complex is now accepted in many cellular systems. The present research emphasizes the role of the beta-gamma complex in G-protein-mediated signal transduction. A structurally divergent neurally expressed G beta subunit, beta-5, was cloned from brain by Mel Simon and coworkers, and later found in an alternatively spliced "long" form in retina (G beta5-L). G beta-5 was recently found to exhibit functional specialization, as it was able to activate PLC but not the MAPK or JNK cascades. Current work in our laboratory examines shared functions of the insect G beta-5 homolog and mammalian G beta-5, using Drosophila melanogaster and cultured PC12 cells as model systems. With respect to G beta-5?s functional specialization, work in collaboration with Zvi Vogel of the Weizmann Institute had previously shown that G beta-5/gamma-2 inhibited adenylyl cyclase (AC) type II, a property novel among G beta-gamma complexes studied to date. This year our collaborative study showed that transfected G beta-5/gamma-2 was again unique among studied beta-gamma combinations in its inability to inhibit AC type VIII, an isoform enriched in brain and implicated in learning and memory.