Potassium channels form the largest ion channel family with over 70 genes identified in humans. 2-pore domain channels (K_2P) are believed to be responsible for background or leak K⁺ currents and they are widely expressed in the nervous system. They are involved in resting potential control and firing pattern of excitable cells¹. The K_2P channel family is comprised of at least 16 members.

The KCNK12 channel (THIK-2, K_2P12.1) has two pore domains (M1 and P1) and a long M1-P1 linker. It has a long cytosolic C terminus and a very unusual N-terminal domain containing many cysteine, proline and arginine residues. This N-terminal domain cannot be found in the similar THIK-1 channel and is highly conserved in mammals.

Until recently, the THIK-2 channel was considered to be a “silent” channel and could not be functionally expressed in mammalian and non-mammalian cell lines. When removing the N-terminal both THIK-1 and THIK-2 channels exhibit similar current-voltage relations. In addition, both channels have 64% identical amino-acids in humans and 59% in rats. Only a small fraction of THIK-2 channel is localized to the cell membrane surface and this can be increased by deleting the original retention/retrieval signal RRR in its N-terminus.

The THIK-2 channel is highly expressed in the cortex, cerebellum hippocampus, thalamus, inferior colliculi of the midbrain and the olfactory bulb. It is also expressed in non-neuronal tissues such as the lungs, liver, kidney and spleen².