G protein-activated inward rectifier potassium channel 4 (GIRK4) (GIRK4)

G protein-activated inward rectifier potassium channel 4 (GIRK4), also known as KCNJ5, is a member of the inward rectifier potassium channel family that plays a pivotal role in regulating cellular excitability (UniProt P48544). It primarily functions as a heterotetramer with GIRK1 to form the IKACh channel in the cardiac atria, where it mediates heart rate slowing in response to parasympathetic acetylcholine release (PubMed: 28468785). In the adrenal cortex, GIRK4 is essential for maintaining the resting membrane potential of zona glomerulosa cells, which is a key step in the regulation of aldosterone biosynthesis (PubMed: 21307304). Mutations in the KCNJ5 gene, particularly gain-of-function somatic mutations, are the most common cause of primary aldosteronism, leading to sodium leak, cell depolarization, and autonomous aldosterone production (NIH: Gene ID 3762). These mutations result in severe hypertension and increased cardiovascular risk, making GIRK4 a high-priority therapeutic target. Pharmacological inhibitors, such as NTC-801, are being investigated for their ability to selectively block these channels to treat atrial fibrillation and primary aldosteronism (PubMed: 28468785). Therapeutic challenges include achieving selectivity over other GIRK subunits to avoid off-target effects on the central nervous system or heart rate (PubMed: 25135136).

Other names

KCNJ5KIR3.4CIRHeart-type inward rectifier potassium channelPotassium channel, inwardly rectifying subfamily J member 5

Selective inhibition of the inward rectifier potassium current to modulate cellular membrane potential and suppress pathological hormone secretion or electrical activity (PubMed: 28468785, PubMed: 21307304).