the heart, IKACh GIRKs are comprised of GIRK1/GIRK4 heterotetramers and GIRK4 homotetramers [7]. In native tissues, G-protein-coupled receptor (GPCR) activation leads to the dissociation of Gβγ subunits from the heterotrimeric G protein complex, and activation of GIRK channels via the binding of Gβγ to the channel (Figure 1A) [8, 9]. In addition to this canonical activation pathway, GIRK channels can be modulated by both exogenous and endogenous small molecules, such as ethanol [10–12] and cholesterol [13, 14], respectively.
