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Proteomic Analysis of Complexes Formed by the Neural G Protein Gαo

Michael R. Koelle, Yale University
Overview: Many drugs of abuse, such as opioids, act by directly binding to G protein coupled receptors or by indirectly affecting neurotransmitter signaling through such receptors. These receptors activate heterotrimeric G proteins in the brain, and understanding addiction thus requires understanding the mechanism of G protein signaling in neurons. The most abundant heterotrimeric G protein in the brain is the one containing the alpha subunit Go, and this is also the specific G protein activated by important receptors involved in addiction, such as the mu opioid receptor. Remarkably, the mechanism by which Go signals remains poorly defined. Receptors activate Go by causing it to bind GTP and release the G protein beta-gamma subunit complex, and the released beta-gamma complex in turn can then regulate certain ion channels. However, it remains unresolved whether Go-GTP itself also binds to target "effectors" to cause additional signaling effects, analogous to how other G protein alpha subunits are known to work. Genetic studies in C. elegans suggest that Go must indeed signal via regulating effectors, not simply via release of the beta-gamma complex.