Nonmigraine-associated TRESK K+ channel variant c110r does not increase the excitability of trigeminal ganglion neurons

Zhaohua Guo, Ping Liu, Fei Ren, Yu Qing Cao

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Recent genetic studies suggest that dysfunction of ion channels and transporters may contribute to migraine pathophysiology. A migraineassociated frameshift mutation in the TWIK-related spinal cord K+ (TRESK) channel results in nonfunctional channels. Moreover, mutant TRESK subunits exert a dominant-negative effect on whole cell TRESK currents and result in hyperexcitability of small-diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache. However, the nonmigraine-associated TRESK C110R variant exhibits the same effect on TRESK currents as the mutant subunits in Xenopus oocytes, suggesting that dysfunction of TRESK is not sufficient to cause migraine. Here, we confirmed that the C110R variant formed nonfunctional channels and exerted a dominant-negative effect on TRESK currents in HEK293T cells, similar to the migraine-associated mutant TRESK. To compare the functional consequences of TRESK mutations/variants in a more physiological setting, we expressed the mutant TRESK and the C110R variant in cultured mouse TG neurons and investigated their effects on background K+ currents and neuronal excitability. Both mutant TRESK and the C110R variant reduced the endogenous TRESK currents in TG neurons, but the effect of the C110R variant was significantly smaller. Importantly, only TG neurons expressing mutant TRESK subunits, but not those expressing the C110R variant, exhibited a significant increase in excitability. Thus only the migraine-associated TRESK mutation, but not the C110R variant, reduces the endogenous TRESK currents to a degree that affects TG excitability. Our results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility.

Original languageEnglish
Pages (from-to)568-579
Number of pages12
JournalJournal of neurophysiology
Issue number3
StatePublished - Aug 1 2014


  • Migraine
  • Neuronal excitability
  • Trigeminal ganglion


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