G-protein-gated inwardly rectifying potassium (GIRK, also referred to as Kir3) channels play an important role in maintaining the resting membrane potential in brain and cardiac cells. Their ability to conduct potassium ions (K+) into the cell more easily than out of the cell is referred to as the property of “inward rectification” (see Glossary). Under physiological conditions, the small outward K+ current through GIRK channels decreases the excitability of the cell [1]. Three types of GIRK subunits (GIRK1, GIRK2, and GIRK3) are expressed in the brain and form either homotetramers of GIRK2, or heterotetramers (e.g., GIRK1 and GIRK2) in different brain regions [2–4]. Although the GIRK1/GIRK2 combination is abundant in the majority of brain regions, dopaminergic neurons in the ventral tegmental area (VTA) express only GIRK2 and GIRK3 subunits, and substantia nigra (SNc) dopaminergic neurons express only GIRK2 [4–6]. In 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
