Correspondence sandoz@unice.fr In BriefRoyal et al. demonstrate that migraineassociated frameshift mutations of TRESK, a two-pore-domain K+ channel, lead to the production of a second protein fragment, which carries the pathophysiological function by inhibiting TREK1 and 2, due to a mechanism called frameshift mutation-induced alternative translation initiation (fsATI).

Twik-related K + channel 1 (TREK1), TREK2, and Twik-related arachidonic-acid stimulated K + channel (TRAAK) form the TREK subfamily of two-pore-domain K + (K 2P ) channels. Despite sharing up to 78% sequence homology and overlapping expression profiles in the nervous system, these channels show major differences in their regulation by physiological stimuli. For instance, TREK1 is inhibited by external acidification, whereas TREK2 is activated. Here, we investigated the ability of the members of the TREK subfamily to assemble to form functional heteromeric channels with novel properties. Using single-molecule pull-down (SiMPull) from HEK cell lysate and subunit counting in the plasma membrane of living cells, we show that TREK1, TREK2, and TRAAK readily coassemble. TREK1 and TREK2 can each heterodimerize with TRAAK, but do so less efficiently than with each other. We functionally characterized the heterodimers and found that all combinations form outwardly rectifying potassium-selective channels but with variable voltage sensitivity and pH regulation. TREK1-TREK2 heterodimers show low levels of activity at physiological external pH but, unlike their corresponding homodimers, are activated by both acidic and alkaline conditions. Modeling based on recent crystal structures, along with mutational analysis, suggests that each subunit within a TREK1-TREK2 channel is regulated independently via titratable His. Finally, TREK1/TRAAK heterodimers differ in function from TRAAK homodimers in two critical ways: they are activated by both intracellular acidification and alkalinization and are regulated by the enzyme phospholipase D2. Thus, heterodimerization provides a means for diversifying functionality through an expansion of the channel types within the K 2P channels.potassium channels | single-molecule fluorescence | leak current | combinatorial diversity | heteromerization

The Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) was not thought to multimerize. Rayaprolu et al. show that Ci-VSP exists as a dimer and that this interaction lowers the voltage dependence of activation and alters substrate specificity.

In mice, disseminated coagulation, inflammation, and ischemia induce neurological damage that can lead to death. These symptoms result from circulating bubbles generated by a pathogenic decompression. Acute fluoxetine treatment or the presence of the TREK-1 potassium channel increases the survival rate when mice are subjected to an experimental dive/decompression protocol. This is a paradox because fluoxetine is a blocker of TREK-1 channels. First, we studied the effects of an acute dose of fluoxetine (50 mg/kg) in wild-type (WT) and TREK-1 deficient mice (knockout homozygous KO and heterozygous HET). Then, we combined the same fluoxetine treatment with a 5-day treatment protocol with spadin, in order to specifically block TREK-1 activity (KO-like mice). KO and KO-like mice were regarded as antidepressed models. In total, 167 mice (45 WTcont 46 WTflux 30 HETflux and 46 KOflux) constituting the flux-pool and 113 supplementary mice (27 KO-like 24 WTflux2 24 KO-likeflux 21 WTcont2 17 WTno dive) constituting the spad-pool were included in this study. Only 7% of KO-TREK-1 treated with fluoxetine (KOflux) and 4% of mice treated with both spadin and fluoxetine (KO-likeflux) died from decompression sickness (DCS) symptoms. These values are much lower than those of WT control (62%) or KO-like mice (41%). After the decompression protocol, mice showed significant consumption of their circulating platelets and leukocytes. Spadin antidepressed mice were more likely to exhibit DCS. Nevertheless, mice which had both blocked TREK-1 channels and fluoxetine treatment were better protected against DCS. We conclude that the protective effect of such an acute dose of fluoxetine is enhanced when TREK-1 is inhibited. We confirmed that antidepressed models may have worse DCS outcomes, but concomitant fluoxetine treatment not only decreased DCS severity but increased the survival rate.

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Il est difficile de comprendre pourquoi des mutations délétères d'un même gène se trouvent être ou ne pas être associées à une maladie. La migraine est une affection neurologique handicapante qui affecte 15 % de la population. Une attaque migraineuse se traduit par des maux de tête d'une durée de 4 à 72 h accompagnés d'une hypersensibilité à de nombreux stimulus, tels que la lumière ou le son, pouvant mener à des nausées, voire des vomissements. La migraine est une maladie complexe liée, entre autres, à l'hyperexcitabilité électrique des neurones sensoriels de la face, appelés neurones trigéminaux. Cette excitabilité électrique est sous le contrôle de canaux ioniques [1] (➜). Les canaux « potassiques à deuxdomaines pore » ou K 2P sont inhibiteurs et servent de frein à l'excitabilité neuronale. Lorsque ces protéines dysfonctionnent, une hyperexcitabilité des neurones survient (Figure 1). Une version mutée du canal TRESK (TWIK-related spinal cord potassium channel) 1 , un membre de la famille des canaux K 2P , présentant une délétion de 2 paires de bases entraînant un décalage du cadre de lecture (frameshift : F139WfsX24), dénommée TRESK-MT, a récemment été incriminée dans la migraine [2]. Cette mutation induit la formation d'un canal tronqué qui, en