Properties, regulation, pharmacology, and functions of the K2P channel, TRESK

TWIK-related spinal cord K+ channel (TRESK) is the gene product of KCNK18, the last discovered leak potassium K-2P channel gene. Under resting conditions, TRESK is constitutively phosphorylated at two regulatory regions. Protein kinase A (PKA) and microtubule affinity-regulating (MARK) kinases can be applied in experiments to phosphorylate these sites of TRESK expressed in Xenopus oocytes, respectively. Upon generation of a calcium signal, TRESK is dephosphorylated and thereby activated by calcineurin. In this process, the binding of calcineurin to the channel by non-catalytic interacting sites is essential. The phosphorylation/dephosphorylation regulatory process is modified by 14-3-3 proteins. Human, but not murine TRESK is also activated by protein kinase C. TRESK is expressed most abundantly in sensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia, and the channel modifies certain forms of nociceptive afferentation. In a large pedigree, a dominant negative mutant TRESK allele was found to co-segregate perfectly with migraine phenotype. While this genetic defect may be responsible only for a very small fraction of migraine cases, specific TRESK activation is expected to exert beneficial effect in common forms of the disease.