We observed some interesting differences between GIRK-dependent signaling in transfected HEK cells and infected Girk2 −/− pyramidal neurons. Notably, GIRK1/GIRK2 channels expressed in HEK cells were more sensitive to GABABR activation (i.e., they exhibited a lower EC50) than the GIRK channels found in wild-type pyramidal neurons or Girk2 −/− neurons expressing GIRK2a or GIRK2c. This difference could be explained by a higher density of receptor and channel expressed in HEK cells, and/or by different receptor-channel ratios achieved in the different cell systems. The difference in coupling efficiency could also reflect the presence of negative regulatory elements in neurons that are not found in HEK cells. Indeed, we reported previously that a complex consisting of RGS7 and Gβ5 decreases the sensitivity of GIRK channels to GABABR activation in hippocampal neurons46–48, while also prominently accelerating GABABR-GIRK current deactivation kinetics. In support of this contention, the deactivation kinetics of GABABR-GIRK currents were significantly faster in neurons than in HEK cells.
