Many modulatory neurotransmitters in the brain, such as dopamine, acetylcholine, serotonin and GABA, inhibit neuronal activity by stimulating G protein-coupled receptors (GPCRs) that couple to G protein-gated inwardly rectifying (GIRK, also referred to as Kir3) channels1. The activation of GIRK channels hyperpolarizes the neuron’s membrane potential, and thereby reduces action potential firing1, 2. GIRK channels are widely expressed in the brain, existing as predominantly heterotetramers of three different GIRK channel subunits, GIRK1, GIRK2 and/or GIRK3, or as homotetramers of the GIRK2 subunit1, 2. GIRK channels have been implicated in the pathophysiology of several human neurological disorders3. Genome-wide association studies (GWAS) of people with schizophrenia have identified single nucleotide polymorphisms (SNPs) in the Kcnj3 (GIRK1) gene4. SNPs in Kcnj6 (GIRK2) have been linked to alcohol and nicotine dependence, reduced opioid withdrawal and increased opioid requirement for analgesia5–8. Recently, a mutation in Kcnj6 has been proposed to contribute to Keppen-Lubinsky syndrome, a severe developmental disorder with cognitive deficits9.
