The level of GIRK1 protein is significantly reduced in the hippocampus of constitutive Girk2 −/− mice15, 24. Our experiments with the GIRK1-selective agonist ML297, however, suggest that viral expression of GIRK2 isoforms in Girk2 −/− pyramidal neurons restored a normal level of functional GIRK1/GIRK2 heteromeric channels. Baclofen-induced currents in Girk2 −/− pyramidal neurons expressing either GIRK2a or GIRK2c were significantly larger than those measured in wild-type controls, however, indicating that some of the GABABR-GIRK current was carried by GIRK2 homomeric or GIRK2/GIRK3 heteromeric channels. Interestingly, expression of GIRK1 in VTA dopamine neurons, which normally express a GIRK2c/GIRK3 heteromeric channel, increased GIRK channel sensitivity to GABABR activation37. Moreover, GIRK2/GIRK3 heteromers are less sensitive to G protein activation than GIRK2 homomers37. Thus, an altered proportion of GIRK1-containing and GIRK1-lacking channels in Girk2 −/− pyramidal neurons expressing GIRK2a or GIRK2c could explain why some features of the baclofen-induced current, including the EC50, differed from those in wild-type neurons. Notably, adenosine and 5HT1AR-dependent currents in Girk2 −/− neurons expressing GIRK2a or GIRK2c did not differ in terms of amplitude from wild-type controls, suggesting that
