Biochemical and molecular genetic experiments indicate that the predominant form of GIRK channels in the brain is a heterotetramer of GIRK1 and GIRK2 subunits19. Whether asymmetric arrangements of GIRK channel heterotetramers, such as a GIRK1-GIRK1-GIRK2-GIRK3, exist in neurons is still not known. Studies with GIRK knockout mice demonstrate that GIRK2 plays a primary role in generating GIRK currents in neurons (Table 1); mice lacking GIRK2 channels exhibit little or no GIRK current in a number of brain regions (Figure 1D, Table 1), including the hippocampus, cerebellum, substantia nigra, locus coeruleus and VTA26-32. Interestingly, GIRK3 knockout mice are indistinguishable from wild-type controls in some behavioral tests33 (e.g. open-field motor activity and motor-coordination) and have similar agonist-induced currents but exhibit less severe withdrawal from sedatives34 and reduced cocaine self-administration35. These findings suggest GIRK3 may have a regulatory role for GIRK signaling in the brain.
