Beta/Gamma Subunit Heterogeniety in G Proteins

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The specificity of G protein signaling in brain is essential for the translation of neurotransmitter activity into meaningful neurological responses. The challenge is to understand how this is accomplished. From the beginning, this grant has focused on how the specificity of signaling is encoded in the subunit structure of the G protein. Historically, the diverse alpha subunits were assumed to specify the roles of the G proteins in particular signaling pathways. However, our recent work has called this assumption into question with the discovery of similarly diverse gamma subtypes whose unique signaling properties were revealed for the first time through the use of a gene targeting approach. During the next funding period, we propose to focus on the Gng7 mouse model to elucidate how deletion of the gamma 7 subtype disrupts the D1 dopamine receptor signaling in brain, and how this signaling defect produces the distinctive phenotype of these mice. The specific aims of this grant are: 1) to identify the nature and full range of the neurological phenotype; 2) to determine the cellular basis for the phenotype; 3) to elucidate the biochemical defects responsible for various aspects of the phenotype; and 4) to investigate the newly discovered role of the gamma 7 subtype in controlling the assembly of the Golf protein. Because dysfunction of D1 dopamine receptor signaling is associated with numerous diseases, including Parkinson's disease, schizophrenia, Tourette's syndrome, Huntington's disease, and alcohol and drug addiction, the fundamental importance and clinical ramifications of this work are enormous.