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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics*
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Gene Expression / genetics
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Migraine Disorders / chemically induced
  • Migraine Disorders / genetics
  • Migraine Disorders / pathology*
  • Migraine Disorders / physiopathology
  • Models, Biological
  • Models, Molecular
  • Mutation / genetics*
  • Neurons / physiology*
  • Neurotransmitter Agents / toxicity
  • Nitric Oxide / toxicity
  • Oocytes
  • Potassium Channels / genetics
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Xenopus


  • Kcnk10 protein, mouse
  • Kcnk18 protein, rat
  • Neurotransmitter Agents
  • Potassium Channels
  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1
  • Nitric Oxide