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Neuron. 2019 Jan 16;101(2):232-245.e6. doi: 10.1016/j.neuron.2018.11.039. Epub 2018 Dec 17.

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

Author information

1
Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France.
2
Neurophysiology Laboratory, Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
3
Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France; Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
4
Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, France.
5
Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France; Neurophysiology Laboratory, Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
6
Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
7
Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France. Electronic address: sandoz@unice.fr.

Abstract

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.

KEYWORDS:

K2P channels; KCNK; alternative translation initiation; frameshift mutation; leak current; neuronal excitability; pain; sensory neuron; single molecule fluorescence

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