TRESK: the lone ranger of two-pore domain potassium channels.

TRESK (TWIK-related spinal cord K(+) channel, KCNK18) belongs to the two-pore domain (K2P) background (leak) potassium channel family. Unlike other K2P channels, TRESK is activated by the calcium signal in heterologous expression systems. The activation is mediated by the calcium/calmodulin-dependent protein phosphatase, calcineurin. TRESK is abundantly expressed in dorsal root and trigeminal ganglia. The active ingredient of Sichuan pepper, sanshool, has been suggested to evoke tingling paresthesia by inhibiting the channel in a mechanoreceptor subpopulation of sensory neurons. Recently, dominant-negative mutation of human TRESK was found to be linked to migraine with aura in a large pedigree. It is hoped that future TRESK agonists may prevent or ameliorate the debilitating symptoms of migraine. It will be interesting to see whether the calcineurin-activated K(+) channel maintains normal excitability in the cerebral cortex thereby arresting cortical spreading depression (CSD), or prevents migraine attack only in the trigeminovascular (TGVS) system.