G protein-coupled inward-rectifier potassium channel (GIRK)

G protein-coupled inward-rectifier potassium (GIRK) channels, also known as Kir3 channels, are a family of lipid-gated ion channels that play a pivotal role in controlling the electrical activity of neurons and cardiac cells. These channels are unique because they are primarily activated by the Gβγ subunits of G proteins, which are liberated when Gi/o-coupled receptors—such as the M2 muscarinic, A1 adenosine, and GABA-B receptors—are stimulated by their respective ligands (UniProt P48549, P48544). In the heart, the muscarinic-gated variant (K_ACh) is a heterotetramer of Kir3.1 and Kir3.4 subunits that mediates the vagal slowing of the heart rate by hyperpolarizing sinoatrial and atrioventricular nodal cells. In the brain, GIRK channels (comprising Kir3.1, Kir3.2, and Kir3.3) regulate neuronal firing rates and are involved in the rewarding effects of drugs and the pathophysiology of seizures (PMID: 30639163). Due to their involvement in atrial fibrillation and various neurological disorders, GIRK channels are significant therapeutic targets. Selective inhibitors like NTC-801 are being investigated for treating cardiac arrhythmias by prolonging the atrial refractory period without affecting ventricular repolarization, while activators are being explored for potential analgesic and anti-epileptic properties (PMID: 29133307).

Other names

Muscarinic-gated inward-rectifier potassium channelK_ACh channelKir3 channelInward rectifier potassium channel subfamily JKCNJ3/KCNJ5 heteromer

GIRK channels are activated by the direct binding of G-protein beta-gamma (Gβγ) subunits, which are released from heterotrimeric G proteins following the stimulation of Gi/o-coupled receptors such as M2 muscarinic or A1 adenosine receptors. This activation leads to an efflux of potassium ions, resulting in membrane hyperpolarization and a reduction in cellular excitability (PMID: 25635021; IUPHAR Guide to Pharmacology).