Post-transcriptional regulation and subcellular localization of G-protein γ7 subunit: implications for striatal...

The striatal D₁ dopamine receptor (D₁R) and A_2a adenosine receptor (A_2aR) signaling pathways play important roles in drug-related behaviors. These receptors activate the G_olf protein comprised of a specific combination of α_olfβ₂γ₇ subunits. During assembly, the γ₇ subunit sets the cellular level of the G_olf protein. In turn, the amount of G_olf protein determines the collective output from both D₁R and A_2aR signaling pathways. This study shows the Gng7 gene encodes multiple γ₇ 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 γ₇ protein. Earlier studies on gene-targeted mice demonstrated loss of γ₇ protein disrupts assembly of the G_olf protein. In the current study, morphological analysis reveals the loss of the G_olf protein is associated with altered dendritic morphology of medium spiny neurons. Finally, behavioral analysis of conditional knockout mice with cell-specific deletion of the γ₇ protein in distinct populations of medium spiny neurons reveals differential roles of the G_olf protein in mediating behavioral responses to cocaine. Altogether, these findings provide a better understanding of the regulation of γ₇ protein expression, its impact on G_olf function, and point to a new potential target and mechanisms for treating addiction and related disorders.