Post-transcriptional regulation and subcellular localization of G-protein γ7 subunit: implications for striatal function and behavioral responses to cocaine.

The striatal D dopamine receptor (DR) and A adenosine receptor (AR) signaling pathways play important roles in drug-related behaviors. These receptors activate the G protein comprised of a specific combination of αβγ subunits. During assembly, the γ subunit sets the cellular level of the G protein. In turn, the amount of G protein determines the collective output from both DR and AR signaling pathways. This study shows the gene encodes multiple γ transcripts differing only in their non-coding regions. In striatum, Transcript 1 is the predominant isoform. Preferentially expressed in the neuropil, Transcript 1 is localized in dendrites where it undergoes post-transcriptional regulation mediated by regulatory elements in its 3' untranslated region that contribute to translational suppression of the γ protein. Earlier studies on gene-targeted mice demonstrated loss of γ protein disrupts assembly of the G protein. In the current study, morphological analysis reveals the loss of the G protein is associated with altered dendritic morphology of medium spiny neurons. Finally, behavioral analysis of conditional knockout mice with cell-specific deletion of the γ protein in distinct populations of medium spiny neurons reveals differential roles of the G protein in mediating behavioral responses to cocaine. Altogether, these findings provide a better understanding of the regulation of γ protein expression, its impact on G function, and point to a new potential target and mechanisms for treating addiction and related disorders.