KCNK18 (also named TWIK-related spinal cord K⁺ channel, TRESK or K_2P18.1) is a member of the 2-pore (2P) domain K⁺ channel family that currently includes 16 members. These channels show little time- or voltage-dependence and are considered to be “leak” or “background” K⁺ channels, thereby generating background currents which help set the membrane resting potential and control cell excitation.¹

The K_2P channels have a signature topology that includes four transmembrane domains and two pore domains with intracellular N- and C- termini. It has been proposed that the functional channel unit is a dimer.

Different K_2P family members are regulated by diverse physical and chemical stimuli including temperature, pH, mechanical stretch, inhalation anesthetics, signaling pathways (PKC and PKA), arachidonic acid, etc.

KCNK18 is the only K_2P channel, known so far, whose current is activated following G_αq-receptor coupled activation. The enhancement of KCNK18 current involves activation of calcineurin (calcium–calmodulin-dependent phosphatase 2B) following the rise in intracellular calcium that occurs subsequent to G_αq activation.²  In addition, KCNK18 is potently activated by clinical concentrations of volatile anesthetics.³

KCNK18 expression in humans is largely restricted to the spinal cord although in rodents it has a broader expression pattern that includes brain, testis and spleen.

KCNK18 represents the most important background K⁺ channel in dorsal root ganglion neurons and hence it has been postulated that it has an important role in acute and chronic pain as well as general anesthesia.