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

The muscarinic acetylcholine-sensitive potassium channel, primarily known as the G protein-activated inward rectifier potassium (GIRK) channel or I(K,ACh), is a heterotetrameric protein complex typically composed of KCNJ3 (GIRK1) and KCNJ5 (GIRK4) subunits. It is predominantly expressed in the atria of the heart and various regions of the central nervous system. In the heart, the channel is activated by acetylcholine released from the vagus nerve, which binds to M2 muscarinic receptors, triggering the release of G-protein beta-gamma subunits that directly open the channel. This action results in potassium efflux, hyperpolarizing the sinoatrial and atrioventricular nodes to slow the heart rate. (Source: PubMed, PMID: 25135974; StatPearls, 'Physiology, Cardiac Potassium Channels'). Beyond its physiological role in cardiac rhythm, the GIRK channel is a significant therapeutic target for atrial fibrillation, where selective blockers are being developed to prolong atrial refractoriness without affecting ventricular repolarization. Mutations in the KCNJ5 gene, which encodes a subunit of this channel, are also a major cause of primary aldosteronism and secondary hypertension due to abnormal sodium permeability in the adrenal cortex. In the brain, GIRK channels modulate neuronal firing and are implicated in the mechanism of action of several neuropsychiatric drugs and drugs of abuse. Consequently, targeting these channels offers potential for treating both cardiac arrhythmias and various neurological disorders. (Source: UniProt, P48544; PubMed, PMID: 30653996).

Other names

Muscarinic-gated potassium channelI(K,ACh) channelKCNJ3/KCNJ5 complexInward rectifier potassium channel 3/5Acetylcholine-activated inward rectifier potassium current

Activation of the channel by G-protein beta-gamma subunits (released upon M2 muscarinic or A1 adenosine receptor stimulation) leads to an efflux of potassium ions, causing cell hyperpolarization. In the heart, this slows the pacemaker potential and shortens the action potential duration. Pharmacological inhibition of the I(K,ACh) current is used to prolong the atrial effective refractory period to treat atrial fibrillation.