Research over the last twenty years has elucidated the molecular and structural determinants of GIRK channel activation and modulation by G proteins (Gα andGβγ, with the emerging concept of the existence of macromolecular signaling complexes. Knockout mice for all four mammalian subunits greatly contributed to the understanding of GIRK functions, namely to regulate the excitability of neurons in a cell autonomous fashion, in-between neighboring neurons by regulating synaptic transmission and also regulating the activity of large-scale networks. While we only begin to understand the role of GIRK channels with different subunit compositions, their respective expression pattern in the brain will give further functional insight. For example, DA neurons of the VTA express a unique GIRK2/3 heteromeric channel that has a particularly low affinity for the Gβγ dimer. More research is needed to link such cellular observations to function and behavior. The development of novel tools, such as light activation of GPCRs (optoXRs)165 that couple to GIRK channels as well as conditional and cell-specific knock-out mouse lines, will be important to further advance our understanding of GIRK function. These tools will
