Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Abstract

Guo Z, Liu P, Ren F, Cao YQ. Nonmigraine-associated TRESK K ϩ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. J Neurophysiol 112: 568 -579, 2014. First published May 7, 2014 doi:10.1152/jn.00267.2014.-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 ϩ (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 ϩ 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.

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

“…This mutation segregated perfectly with the MA phenotype in a large pedigree and was shown to produce a non-functional protein that can serve as a dominant negative that functionally downregulates the wildtype (WT) TRESK channel (Lafreniè re et al, 2010;Wood, 2010). TRESK-MT has been shown to induce hyperexcitability of TG neurons (Guo et al, 2014;Liu et al, 2013), which likely underscores its role in migraine. However, in subsequent genetic screening studies, another missense TRESK variant, C110R, was identified (Andres-Enguix et al, 2012).…”

“…Together, these data show that TRESK-MT can inhibit TRESK, TREK1, and TREK2, whereas TRESK-C110R is only able to inhibit TRESK. Based on the fact that TRESK-MT, but not TRESK-C110R, is able to induce TG neuron hyperexcitability (Guo et al, 2014;Liu et al, 2013), we hypothesized that TRESK-MT induces sensory neuron hyperexcitability primarily by acting on TREK1 and TREK2, not TRESK.…”

“…TRESK-C110R, similar to TRESK-MT, exerts a dominant-negative effect on WT-TRESK in heterologous cells, but expression of this mutant was found to have no effect on TG excitability (Guo et al, 2014). This absence of effect explains why this mutant was found in both migraine patients and control subjects (Guo et al, 2014). Therefore, despite the fact that both mutations lead to the same apparent effect on TRESK function, only TRESK-MT is able to increase TG excitability and is linked to migraine pathophysiology.…”

“…However, in subsequent genetic screening studies, another missense TRESK variant, C110R, was identified (Andres-Enguix et al, 2012). TRESK-C110R, similar to TRESK-MT, exerts a dominant-negative effect on WT-TRESK in heterologous cells, but expression of this mutant was found to have no effect on TG excitability (Guo et al, 2014). This absence of effect explains why this mutant was found in both migraine patients and control subjects (Guo et al, 2014).…”

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

“…However, it is important to note that other missense mutations in TRESK channels, including one which resulted in complete lack of channel function (C110R), did not show a correlation with the presence of migraine in patients ( [3], see also [40,62]). …”