Another difference between HEK cell and neuron models is the presence of GIRK3, which has been reported to decrease the activity and surface trafficking of GIRK1/GIRK2 heteromers and GIRK2 homomers in expression systems22, 49. We show here that while the relative dendritic labeling patterns for GIRK2a and GIRK2c were comparable in Girk2 −/− and Girk2 −/− /Girk3 −/− neurons, GPCR-GIRK currents measured in Girk2 −/− /Girk3 −/− neurons expressing GIRK2a or GIRK2c were larger than those measured in Girk2 −/− neurons. These results are consistent with the possible role of GIRK3 as a negative regulator of GIRK channel surface trafficking. In midbrain DA neurons, GIRK3 mediates an interaction between the GIRK channel, a GIRK2c/GIRK3 heteromer13, and SNX-2736, 50, 51, a protein implicated in the surface trafficking and internalization of several channels and receptors52–56. The interaction between SNX-27 and GIRK3 is conferred by a Class I PDZ interaction domain at the GIRK3 C-terminus, which is identical to that found in GIRK2c33. At present, the relevance of SNX-27 and GIRK3 to GIRK channel trafficking in hippocampal neurons is unclear.
