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 between L55C and L333C and lead to sustained activation (Mahajan et al., 2013). According to this model, Gβγ binds to the GIRK channel at the cleft formed by the βD-βE and βL-βM loop from adjacent GIRK subunits, stabilizing the open conformation of the G loop gate that precedes channel opening and ion permeation. Remarkably, the region of Gβγ interaction overlaps completely with the alcohol pocket (Bodhinathan and Slesinger, 2013). GIRK channels are also regulated (but not activated) by Gα subunits (Ivanina et al., 2004; Clancy et al., 2005; Rubinstein et al., 2007). Interestingly, NMR experiments suggest a different region of the cytoplasmic domain is involved (Mase et al., 2012).
