TASK potassium channels and their anesthetic sensitivity

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A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature Medicine, 2010(advance online publication

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms 1 . A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia 2 . We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migrainesalient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominantnegative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target. Migraine is a common recurrent headache disorder, with an annual prevalence estimated at 18.2% in females and 6.5% in males 1 . One third of attacks, which can last from 4 to 72 h, are preceded by transient neurological disturbances known as aura. These are commonly visual, taking the form of scintillating shapes, hallucinations or black spots. Cortical spreading depression (CSD) underlies the aura, and, although its precise relationship to headache is unclear, there is evidence in rats that CSD can activate trigeminal nociceptors 3,4 . During a migraine headache, trigeminal ganglion nerve afferents innervating the meningeal nociceptors secrete pro-inflammatory peptides (such as CGRP and substance P) that cause local inflammation, intensify activatio