Multiple forms of plasticity involving GIRK-dependent signaling in hippocampal neurons have been reported. For example, Jan and colleagues showed that stimuli capable of inducing long-term potentiation (LTP) also enhanced GABABR-GIRK signaling in CA1 pyramidal neurons57. Subsequently, this group showed that NMDA receptor activation triggered a rapid increase in surface trafficking of GIRK channels in hippocampal cultures58, 59. This adaptation involved the dephosphorylation of an N-terminal GIRK2 residue (Ser-9) found in both GIRK2a and GIRK2c, and yielded enhanced basal GIRK channel activity and GIRK channel responses to adenosine receptor activation, but had no effect on GABABR-GIRK signaling. Slesinger and colleagues showed that prolonged morphine treatment in hippocampal cultures shifted the subcellular distribution of GIRK2 from dendritic shafts to spines, leading to enhanced basal and 5HT-induced GIRK currents, but no change in GABABR-GIRK signaling35. Our data suggest that this morphine-induced adaptation does not require elements within the Girk2 promoter or untranslated domains in the Girk2 mRNAs, as only coding sequence was included in the viral reconstitution vectors. The unique GIRK2c C-terminus is also not required, as both GIRK2a and GIRK2c were similarly
