Recent studies have begun to investigate the regulation and localization of GIRK channels expressed in their native environment. In cerebellar granule cells, biochemically restricting the movement of μ opioid receptors does not alter the rate of GIRK activation, revealing that these signaling proteins are localized in membrane compartments and are not freely diffusing in the membrane97. Using neuronal PC12 cells, it was discovered that chronic stimulation of endogenous M2 muscarinic (M2R) receptors leads to down regulation of both the receptors and GIRK channels108, indicating M2R and GIRK are co-regulated in a complex. Furthermore, the GABABR2 subunit has been shown to dimerize with the M2R and form an even larger functional M2R/GABABR2/GIRK heteromeric complex109. Electron microscopic (EM) immunohistochemical studies with brain tissue provide information on the localization of native GIRK channels. In hippocampus, GIRK channels are expressed on the dendritic shafts of hippocampal neurons110, which has been confirmed by cell-attached patch-clamp recordings111. In addition to the shaft, immuno-gold labeling show a tight association of GIRK channels and GABAB receptors on dendritic spines110. In the cerebellum, immunoelectron microscopy studies show that GIRK2/GIRK3
