restored GABABR-GIRK currents to wild-type levels, indicating that the essential proteins needed for GABABR-activated GIRK signaling are present once GIRK channels are expressed on the plasma membrane. The simplest explanation for the reduced GABABR-activated GIRK currents is that fewer GIRK channels traffic to the plasma membrane in the SNX27 KO mice. Thus, maximal activation of GIRK channels by intracellular GTPγS application, which bypasses GPCR activation, is lower in DA neurons lacking SNX27. Restoration of GABABR-activated GIRK currents with a GIRK2 variant (GIRK2a) lacking the PDZ binding motif needed to associate with the PDZ domain of SNX27 suggests that SNX27 is required for forward trafficking and/or maintenance of GIRK2c/3 subunits on the plasma membrane. This regulation may be restricted to PDZ-containing proteins since general endosomal trafficking appears to remain intact in the absence of SNX27 (Cullen and Korswagen, 2011).
