G protein-activated inwardly rectifying potassium channel (GIRK) (GIRK)

G protein-activated inwardly rectifying potassium (GIRK) channels are a family of lipid-gated ion channels that play a fundamental role in regulating cellular excitability across the nervous system and the heart [1.1.1, 1.4.1]. These channels are primarily activated by the Gβγ subunits of inhibitory G proteins (Gi/o) following the stimulation of various G protein-coupled receptors (GPCRs), such as opioid, muscarinic M2, and GABA-B receptors [1.1.1, 1.4.3]. Upon activation, GIRK channels allow the efflux of potassium ions, leading to membrane hyperpolarization and a subsequent decrease in the firing rate of neurons or pacemaker cells [1.1.2, 1.4.1]. Dysregulation of GIRK channel activity is implicated in a wide range of pathologies, including epilepsy, chronic pain, drug addiction, and cardiac arrhythmias like atrial fibrillation [1.2.1, 1.2.2]. Consequently, they are viewed as promising therapeutic targets; activators are being explored for their anticonvulsant and analgesic properties, while selective blockers are under investigation for treating heart rhythm disorders [1.3.1, 1.4.4]. However, the development of GIRK-targeted therapies faces challenges related to subunit selectivity and the potential for off-target effects in the heart or brain [1.2.2, 1.4.5].

Other names

Kir3Kir3.1Kir3.2Kir3.3Kir3.4KCNJ3KCNJ6KCNJ9KCNJ5G protein-gated inwardly rectifying potassium channel

GIRK channels are activated by G-protein beta-gamma subunits following GPCR stimulation, leading to potassium efflux and membrane hyperpolarization, which inhibits cellular firing [1.1.1, 1.4.1].