Acetylcholine-activated inward rectifier potassium channel (GIRK)

Acetylcholine-activated inward rectifier potassium channels, commonly known as GIRK channels, are a family of ion channels that play a critical role in regulating cellular excitability in the heart and central nervous system (UniProt: P48549, P48544). These channels are unique because they are directly gated by the G-beta-gamma subunits released from G-protein-coupled receptors, such as the M2 muscarinic and A1 adenosine receptors (IUPHAR/BPS Guide to PHARMACOLOGY). In the heart, activation of these channels by acetylcholine leads to an efflux of potassium ions, causing membrane hyperpolarization and a subsequent decrease in heart rate and atrial contractility (PubMed: 25635020). Pathologically, the constitutive activation of these channels is a key driver in the pathogenesis of atrial fibrillation, making them a significant target for anti-arrhythmic therapy (PubMed: 30135018). In the brain, GIRK channels modulate neuronal firing and are involved in the mechanisms of pain, addiction, and epilepsy. Therapeutic strategies include the development of selective blockers to treat cardiac arrhythmias and activators to manage neurological conditions, though achieving tissue specificity remains a primary therapeutic challenge.

Other names

G protein-coupled inwardly-rectifying potassium channelK_ACh channelKir3 channelG protein-activated inward rectifier potassium channelKCNJ3/KCNJ5 heterotetramer

Activation by G-protein beta-gamma (Gβγ) subunits following GPCR stimulation (e.g., M2 muscarinic or A1 adenosine receptors) leads to potassium efflux and membrane hyperpolarization.