G-protein-activated inwardly rectifying potassium channel 4 (GIRK4)

G-protein-activated inwardly rectifying potassium channel 4 (GIRK4, gene symbol KCNJ5) is an ion channel protein predominantly expressed in the heart, especially in atrial myocytes, where it co-assembles with GIRK1 to form functional heterotetramers that mediate the IKACh current during vagal stimulation[2][3]. GIRK4 can also function as a homotetramer. The channel is directly activated by Gβγ subunits released from G protein-coupled receptor signaling, such as that initiated by muscarinic acetylcholine receptors in cardiac tissue[1][2]. This activation leads to hyperpolarization of the cell membrane and reduces excitability, serving as the primary effector for parasympathetic regulation of heart rate. GIRK4 structure features two membrane-spanning segments and a selectivity filter for potassium ions. Pathologically, mutations in its encoding gene (KCNJ5) are linked to hypertension through adrenal conditions and are implicated in cardiac arrhythmogenic syndromes. Pharmacologically, casual blockade or modulation of the channel can lead to significant therapeutic and safety consequences, particularly in the context of arrhythmia management and neurophysiological disorders. Unlike classic ligand-gated ion channels, GIRK4's gating is tightly controlled by G protein signaling and phosphorylation states, providing a sophisticated integration node for cellular signaling[1][2][3].

Other names

GIRK4Kir3.4KCNJ5 (gene name)G-protein-gated inward rectifier potassium channel 4G protein-coupled inwardly-rectifying potassium channel 4

Potentiation or inhibition of channel activity via Gβγ subunits downstream of G protein-coupled receptor activation Blockade of the channel pore (e.g., by peptide toxins) Modulation by phosphorylation: channel activity can be increased by PKA-mediated phosphorylation and decreased by PP2A-mediated dephosphorylation