G protein-activated inward rectifier potassium channel 2 (GIRK2) (GIRK2)

G protein-activated inward rectifier potassium channel 2 (GIRK2), encoded by the KCNJ6 gene, is a critical membrane protein that modulates cellular excitability in the central nervous system [1, 2]. It acts as a primary effector for various G protein-coupled receptors (GPCRs), including opioid, GABA-B, and dopamine receptors, by opening in response to the binding of G-beta-gamma subunits [6, 12]. This activation facilitates the efflux of potassium ions, resulting in membrane hyperpolarization and the inhibition of neuronal firing [10, 16]. GIRK2 is widely expressed in the brain, where it exists as homotetramers or heterotetramers with other subunits like GIRK1 and GIRK3 [12, 17].\n\nDysfunction of GIRK2 is linked to several neurological and developmental disorders. Mutations in KCNJ6 cause Keppen-Lubinsky syndrome, characterized by severe developmental delay and intellectual disability [2, 13]. Additionally, GIRK2 overexpression is a significant factor in the cognitive impairments associated with Down syndrome [8, 9]. The channel is also involved in the pathophysiology of neuropathic pain, epilepsy, and substance use disorders, particularly alcohol and nicotine addiction [9, 12]. While GIRK2 represents a promising therapeutic target for analgesia and neurological conditions, drug development faces challenges in achieving subunit selectivity to avoid off-target effects, such as cardiac arrhythmias mediated by related GIRK channels in the heart [6, 12].

Other names

KCNJ6Inward rectifier K(+) channel Kir3.2BIR1KATP-2hiGIRK2KCNJ7

Activation of the channel by G-protein beta-gamma subunits (released from Gi/o-coupled GPCRs) leads to potassium efflux, causing membrane hyperpolarization and inhibition of cellular excitability [6, 12, 16].