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.
In this issue of Neuron, Royal et al.(2018) find that a mutant form of the TRESK ion channel linked to migraine undergoes alternative translation to produce an inhibitory protein that blocks TREK channels, leading to neuronal hyperexcitability and migraine in rodents.
Tandem pore domain weak inward rectifier potassium channel (TWIK)-related spinal cord K⁺ (TRESK; K<sub>2P</sub>18.1) channel is the only member of the two-pore domain K⁺ (K<sub>2P</sub>) channel family that is activated by an increase in intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and linked to migraines.
This review will focus on the genetics of migraine with particular emphasis placed on the potentially important role genes HEPH (responsible for iron transport and homeostasis) and KCNK18 (important for the transport and homeostasis of potassium) play in migraine cause.
A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned.
In this study, three common polymorphisms in the KCNK18 gene were analysed for genetic variation in an Australian case-control migraine population consisting of 340 migraine cases and 345 controls.
In situ hybridization studies of the mouse Kcnk18 ortholog show that it is developmentally expressed in the trigeminal and dorsal root ganglia, further supporting the involvement of this gene in migraine pathogenesis.
This review will elaborate on the possible role of the TRESK channel in regulating neuronal excitability, its role in migraine pathogenesis, and on promising therapeutic opportunities targeting this channel.
A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned.
Recently, a mutation in the KCNK18 gene, encoding the TRESK two-pore domain potassium channel, was described in a large family with migraine with aura.
These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.
We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model.