The primary pathway for GIRK channel activation occurs through stimulation of GPCRs that couple to pertussis-toxin sensitive G proteins (Gi/o), which in turn directly activate GIRK channel via G protein Gβγ subunits (Logothetis et al., 1987; Reuveny et al., 1994; Wickman et al., 1994; Huang et al., 1995; Kunkel and Peralta, 1995). Mutagenesis and biochemical Gβγ binding experiments implicated several regions in the cytoplasmic domains involved in Gβγ activation, with a particular emphasis on the involvement of a Leucine in the βL-βM loop (L344 in GIRK2, L333 in GIRK1) (Huang et al., 1995, 1997; He et al., 1999; Ivanina et al., 2003; Finley et al., 2004). Whorton and MacKinnon (2013) recently solved the crystal structure of a GIRK2-Gβγ complex and confirmed that L344 interacts directly with the Gβ subunit. Leu55 on Gβ forms hydrogen bonds with L344 as well as with several other sites near the alcohol pocket (F254, P256, L342, and Y349). Similarly, taking a computational approach, Mahajan et al. (2013) recently pinpointed an interaction between L55 in Gβ and L333 in GIRK1, demonstrating that a disulfide can form
