GIRK4

GIRK4, also known as Kir3.4, is a member of the inward-rectifier potassium channel (Kir) family. It is encoded in humans by the KCNJ5 gene and contributes to the assembly of G protein-activated inwardly rectifying potassium (GIRK) channels, which are activated by G protein beta-gamma subunits following Gi/o-coupled receptor stimulation.

GIRK4 channels form tetramers, which can be homomeric or heteromeric with other GIRK subunits such as GIRK1. The channel activity is regulated by intracellular Gβγ subunits released after activation of Gi/o-coupled receptors (for example muscarinic M2 receptors). Upon opening, GIRK4-containing channels allow potassium efflux, producing hyperpolarization and reduced cellular excitability. The specific subunit composition of a GIRK channel influences its biophysical properties and tissue distribution, with GIRK1/4 heterotetramers playing a prominent role in certain cardiac tissues.

Physiologically, GIRK channels contribute to the inhibitory control of neuronal signaling and to the parasympathetic regulation of heart rate. In the heart, IKACh currents generated by GIRK1/4 channels participate in acetylcholine-mediated slowing of the heart rate by stabilizing the resting membrane potential of atrial cells. In the brain, GIRK channels modulate synaptic transmission and neuronal excitability across various regions.

Clinically, mutations in KCNJ5 have been linked to primary aldosteronism and familial hyperaldosteronism. Certain activating mutations reduce ion selectivity, permitting sodium influx and depolarization of adrenal zona glomerulosa cells, increasing intracellular calcium and aldosterone production. Altered GIRK4 function has also been associated with cardiac arrhythmias in some studies, reflecting the channel’s role in cardiac electrophysiology.