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Two‐pore domain (K2P) potassium channels are important regulators of cellular electrical excitability. However, the structure of these channels and their gating mechanism, in particular the role of the bundle‐crossing gate, are not well understood. Here, we report that quaternary ammonium (QA) ions bind with high‐affinity deep within the pore of TREK‐1 and have free access to their binding site before channel activation by intracellular pH or pressure. This demonstrates that, unlike most other K + channels, the bundle‐crossing gate in this K2P channel is constitutively open. Furthermore, we used QA ions to probe the pore structure of TREK‐1 by systematic scanning mutagenesis and comparison of these results with different possible structural models. This revealed that the TREK‐1 pore most closely resembles the open‐state structure of KvAP. We also found that mutations close to the selectivity filter and the nature of the permeant ion profoundly influence TREK‐1 channel gating. These results demonstrate that the primary activation mechanisms in TREK‐1 reside close to, or within the selectivity filter and do not involve gating at the cytoplasmic bundle crossing. K2P potassium channels are important regulators of cellular excitability. This study reveals that in contrast to most other K+ channels the primary gating mechanism in the K2P channel TREK‐1 does not involve opening and closure of the cytoplasmic bundle crossing, but takes place close to or within the selectivity filter.

Migraine headaches are a debilitating condition that affect many individuals. Now, Guy Rouleau and his colleagues link loss-of-function mutations in a potassium channel protein with a particular migraine syndrome in humans. 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 migraine-salient 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 dominant-negative 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.

A loss of function mutation in the TRESK K2P potassium channel ( KCNK18 ), has recently been linked with typical familial migraine with aura. We now report the functional characterisation of additional TRESK channel missense variants identified in unrelated patients. Several variants either had no apparent functional effect, or they caused a reduction in channel activity. However, the C110R variant was found to cause a complete loss of TRESK function, yet is present in both sporadic migraine and control cohorts and no variation in KCNK18 copy number was found. Thus despite the previously identified association between loss of TRESK channel activity and migraine in a large multigenerational pedigree, this finding indicates that a single non-functional TRESK variant is not alone sufficient to cause typical migraine and highlights the genetic complexity of this disorder.