Remarkably, lack of SNX27 protein in VTA DA neurons appeared to have a greater effect on GABABR-activated GIRK currents than D2R-activated GIRK currents. Thus, D2R and GABABR signaling complexes may be differentially regulated in DA neurons. GABAB receptors have been shown to form macromolecular complexes with muscarinic receptors (Boyer et al., 2009), extracellular calcium sensing receptor (Chang et al., 2007) and GIRK channels (Ciruela et al., 2010; Fowler et al., 2007; Labouèbe et al., 2007; Lujan et al., 2009; Zhou et al., 2012). It is unknown whether D2 receptors also form distinct complexes with GIRK channels in DA neurons. GPCRs can be distinctly regulated based on compartmentalization or access to regulatory elements (Gainetdinov et al., 2004). Another possibility is that D2R and GABABR couple to different subunit compositions of GIRK channels. For example, D2 receptors may selectively activate GIRK2 homotetramers, while GABAB receptors may couple to GIRKc2-GIRK3 heteromultimers. Accordingly, SNX27 preferential association with GIRK2c/3 (Lunn et al., 2007) would selectively target GABABR-activated GIRK channels. In support of this idea, expression of GIRK2a in DA neurons lacking SNX27 led to slightly
