Regulation of two-pore-domain potassium TREK channels and their involvement in pain perception and migraine.

The ability to sense pain signals is closely linked to the activity of ion channels expressed in nociceptors, the first neurons that transduce noxious stimuli into pain. Among these ion channels, TREK1, TREK2 and TRAAK from the TREK subfamily of the Two-Pore-Domain potassium (K2P) channels, are hyperpolarizing channels that render neurons hypoexcitable. They are regulated by diverse physical and chemical stimuli as well as neurotransmitters through G-protein coupled receptor activation. Here, we review the molecular mechanisms underlying these regulations and their functional relevance in pain and migraine induction.

TREK channel activation suppresses migraine pain phenotype.

Activation and sensitization of trigeminal ganglia (TG) sensory neurons, leading to the release of pro-inflammatory peptides such as calcitonin gene-related peptide (CGRP), are likely a key component in migraine-related headache induction. Reducing TG neuron excitability represents therefore an attractive alternative strategy to relieve migraine pain. Here by using pharmacology and genetic invalidation ex vivo and in vivo, we demonstrate that activating TREK1 and TREK2 two-pore-domain potassium (K2P) channels inhibits TG neuronal firing sufficiently to fully reverse the migraine-like phenotype induced by NO-donors in rodents. Finally, targeting TREK is as efficient as treatment with CGRP antagonists, which represents one of the most effective migraine therapies. Altogether, our results demonstrate that inhibiting TG excitability by pharmacological activation of TREK channels should be considered as an alternative to the current migraine treatment.

Migraine and Two-Pore-Domain Potassium Channels.

Migraine is a common, disabling neurological disorder with a genetic, environmental, and hormonal component with an annual prevalence estimated at ~15%. It is characterized by attacks of severe, usually unilateral and throbbing headache, and can be accompanied by nausea, vomiting, and photophobia. Migraine is clinically divided into two main subtypes: migraine with aura, when it is preceded by transient neurological disturbances due to cortical spreading depression (CSD), and migraine without aura. Activation and sensitization of trigeminal sensory neurons, leading to the release of pro-inflammatory peptides, is likely a key component in headache pain initiation and transmission in migraine. In the present review, we will focus on the function of two-pore-domain potassium (K2P) channels, which control trigeminal sensory neuron excitability and their potential interest for developing new drugs to treat migraine.

KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies.

Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its ß-auxiliary subunit KCNE1 to generate the slow cardiac potassium IKs current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily. Strikingly, assembly with KCNE1 switches TMEM16A from a calcium-dependent to a voltage-dependent ion channel. Importantly, clinically relevant inherited mutations within the TMEM16A-regulating domain of KCNE1 abolish the TMEM16A modulation, suggesting that the TMEM16A-KCNE1 current may contribute to inherited pathologies. Altogether, these findings challenge the dogma of the specificity of auxiliary subunits regarding protein complexes and questions ion channel classification.

TREK for High-Speed and High-Frequency Conduction through the Axon.

In this issue of Neuron, Kanda et al. (2019) find that the two-pore domain potassium channels TRAAK and TREK1 drive axonal action potential repolarization for high-speed and high-frequency nervous impulses in mammalian myelinated nerves.

[Two-pore-domain potassium channels and molecular mechanisms underlying migraine]. / Canaux potassiques à deux domaines P (K2P) et migraine.

Migraine is a common, disabling neurological disorder with genetic, environmental and hormonal components and a prevalence estimated at ∼15%. Migraine episodes are notably related, among several factors, to electric hyperexcitability in sensory neurons. Their electrical activity is controlled by ion channels that generate current, specifically by the two-pore-domain potassium, K2P, channels, which inhibit electrical activity. Mutation in the gene encoding TRESK, a K2P channel, causes the formation of TRESK-MT1, the expected non-functional C-terminal truncated TRESK channel, and an additional unexpected protein, TRESK-MT2, which corresponds to a non-functional N-terminal truncated TRESK channel, through a mechanism called frameshift mutation-induced Alternative Translation Initiation (fsATI). TRESK-MT1 is inactive but TRESK-M2 targets two other ion channels, TREK1 and TREK2, inducing a great stimulation of the neuronal electrical activity that may cause migraines. These findings identify TREK1 and TREK2 as potential molecular targets for migraine treatment and suggest that fsATI should be considered as a distinct class of mutations.

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK.

It is often unclear why some genetic mutations to a given gene contribute to neurological disorders and others do not. For instance, two mutations have previously been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2-bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here, we identify a new mechanism, termed frameshift mutation-induced alternative translation initiation (fsATI), that may explain why only TRESK-MT is associated with migraine. fsATI leads to the production of a second protein fragment, TRESK-MT2, which co-assembles with and inhibits TREK1 and TREK2, two other two-pore-domain K+ channels, to increase trigeminal sensory neuron excitability, leading to a migraine-like phenotype in rodents. These findings identify TREK1 and TREK2 as potential molecular targets in migraine and suggest that fsATI should be considered as a distinct class of mutations.