A causal role for TRESK loss of function in migraine mechanisms
Summary
The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. 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. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
| Authors | Pettingill P, Weir GA, Wei T, Wu Y, Flower G, Lalic T, Handel A, Duggal G, Chintawar S, Cheung J, Arunasalam K, Couper E, Haupt LM, Griffiths LR, Bassett A, Cowley SA, Cader MZ |
|---|---|
| Journal | Brain : a journal of neurology |
| Publication Date | 2019 Dec 1;142(12):3852-3867 |
| PubMed | 31742594 |
| PubMed Central | PMC6906598 |
| DOI | 10.1093/brain/awz342 |