An emerging theme with GIRK signaling is that GPCRs, G-proteins and GIRK channels exist in a macromolecular signaling complex [25] (Figure 1). Now, recent studies suggest that RGS proteins and GIRK channels may also interact directly within this complex. For example the degradation-resistant RGS4 co-precipitates with several GPCRs and GIRKs forming stable macromolecular complexes, while RGS3s does not interact with the GPCR-GIRK channel complex [26]. These observations suggest a “precoupling” model in the case of RGS4 versus a “collision coupling” model for RGS3. “Precoupling” can accelerate GIRK channel gating with a 100-fold higher potency [26]. Further support for a macromolecular complex comes from fluorescence resonance energy transfer (FRET) studies that demonstrate the interaction between RGS4 and GABAB R1 or R2 subunits [27], or between RGS2 and GIRK3 but not GIRK2 [2]. Thus, a subset of RGS proteins appears to interact selectively with GIRK channels.
