Having high-resolution structures of GIRK channels provides key information on the structural context of sites previously identified for G protein regulation. GIRK channels are predominantly closed at resting membrane potentials (agonist-independent, basal activity) and become activated upon stimulation of PTX-sensitive Gi/o G proteins (receptor-induced current). Both forms of activation involve binding of Gβγ directly to the GIRK channel8,9,36,75. Functional and biochemical studies have identified sequences in the N- and C-terminal domains of GIRK1-4 that are involved in both agonist-independent and receptor-induced Gβγ activation9,75-82 (Figure 2A,B). In particular, a Leu (GIRK1-L333, GIRK2-L344, GIRK4-L339) in the C-terminal domain of GIRK channels (βL-βM sheet) appears to have a critical role in the Gβγ-dependent activation of GIRK channels77,80,81. Similarly, functional and biochemical studies have pinpointed Gα binding domains in the N- and C-terminal domains of GIRK channels82-85,99.
