G protein-activated inward rectifier potassium channel 2 (Kir3.2) (Kir3.2)

G protein-activated inward rectifier potassium (GIRK) channels, particularly the Kir3.2 (GIRK2) subunit, are essential regulators of membrane potential and cellular excitability in the brain and heart [1, 3]. These channels are unique because they are directly gated by the Gβγ subunits released from heterotrimeric G proteins upon the activation of various G protein-coupled receptors (GPCRs), such as GABA-B, opioid, and muscarinic M2 receptors [2, 5]. In the central nervous system, Kir3.2 is a major component of both homomeric and heteromeric (e.g., Kir3.1/Kir3.2) channels that mediate slow inhibitory postsynaptic potentials, thereby dampening neuronal firing [3]. Mutations in the KCNJ6 gene, which encodes Kir3.2, are associated with Keppen-Lubinsky syndrome and have been implicated in the pathogenesis of epilepsy and Down syndrome [1, 4]. Furthermore, Kir3.x channels in the heart (specifically Kir3.1/Kir3.4) are critical for the vagal regulation of heart rate, making them targets for treating atrial fibrillation [2, 3]. Pharmacological agents like the selective activator ML297 or various channel blockers are being explored for their potential to treat pain, anxiety, and cardiac disorders [4]. However, therapeutic development is challenged by the need for high subtype selectivity to avoid adverse effects like bradycardia or neurological impairment [3, 5].

Other names

GIRK2KCNJ6Inward rectifier K(+) channel Kir3.2Birk-1HIWOC2KCNJ7KCNJ3KCNJ5

Drugs act as either activators (openers) or inhibitors (blockers) of the channel pore or its G-protein coupling site. Activation leads to potassium efflux and membrane hyperpolarization, while inhibition prevents this inhibitory current, increasing cellular excitability.