A causal role for TRESK loss of function in migraine mechanisms

Pettingill, Philippa; Weir, Greg A.; Wei, Tina; Wu, Yukyee; Flower, G.; Lalic, Tatjana; Handel, Adam E.; Duggal, Galbha; Chintawar, Satyan; Cheung, Jonathan; Arunasalam, Kanisa; Couper, Elizabeth; Haupt, Larisa M.; Griffiths, Lyn R.; Bassett, Andrew; Cowley, Sally A.; Cader, M Z

doi:10.1093/brain/awz342

Cited by 53 publications

(69 citation statements)

References 38 publications

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“…When tested in DRG sensory neurons, cloxyquin also increased the background K + current in a subset of neurons, indicating that it is able to activate native channels [68,75]. As mentioned earlier, cloxyquin reduced spontaneous firing in iPSC-derived nociceptors carrying the F1449V gain-of-function mutation in Nav1.7, but, more importantly, this drug reduced mechanical and thermal hypersensitivity in a mouse model of migraine by administration of nitroglycerine [61]. The identification of cloxyquin and its in vitro and in vivo effects reinforce the therapeutic potential of targeting TRESK for analgesic purposes and opens the door to find new and selective compounds to activate the channel for the treatment of migraine or other pain-related diseases.…”

Section: Tresk Modulation and Pharmacology: Therapeuticssupporting

confidence: 52%

“…Finally, the authors showed the therapeutic possibilities of enhancing TRESK activity. Cloxyquin, a TRESK activator that will be discussed in the next chapter, was able to reduce spontaneous firing in iPSC-derived nociceptors carrying the F1449V gain-of-function mutation in Nav1.7, that causes erythromelalgia [61]. In addition, in a rodent model of migraine generated by administration of nitroglycerine, cloxyquin treatment was able to reduce mechanical and thermal hypersensitivity, highlighting the potential of TRESK as an analgesic drug target.…”

Section: Tresk and Migrainementioning

confidence: 98%

“…In a recent study, human nociceptors with the F139WfsX24 mutation were generated from induced pluripotent stem cells from migraine patients [61]. Non-peptidergic nociceptors containing the mutation showed an increased excitability compared to these obtained from healthy control subjects.…”

Section: Tresk and Migrainementioning

confidence: 99%

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The Background K+ Channel TRESK in Sensory Physiology and Pain

Andrés‐Bilbé

Castellanos

Pujol-Coma

et al. 2020

IJMS

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TRESK belongs to the K2P family of potassium channels, also known as background or leak potassium channels due to their biophysical properties and their role regulating membrane potential of cells. Several studies to date have highlighted the role of TRESK in regulating the excitability of specific subtypes of sensory neurons. These findings suggest TRESK could be involved in pain sensitivity. Here, we review the different evidence available that involves the channel in pain and sensory perception, from studies knocking out the channel or overexpressing it to identified mutations that link the channel to migraine pain. In addition, the therapeutic possibilities are discussed, as targeting the channel seems an interesting therapeutic approach to reduce nociceptor activation and to decrease pain.

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Section: Tresk Modulation and Pharmacology: Therapeuticssupporting

confidence: 52%

Section: Tresk and Migrainementioning

confidence: 98%

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The Background K+ Channel TRESK in Sensory Physiology and Pain

Andrés‐Bilbé

Castellanos

Pujol-Coma

et al. 2020

IJMS

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“…Therefore, we employed the TRESK knock-out (TRESK −/− ) mouse model to assess alterations in SCN electrical properties, molecular changes and behavioural output. Furthermore, we demonstrate that K2Ps are critically important for the correct cellular state and responses of the SCN, which has implications for the growing list of disorders that involve K2Ps and for novel pharmacological interventions that may target these ion channels 8,9 .…”

mentioning

confidence: 91%

TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses

et al. 2020

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The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours.

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“…This might be the reason why only specific frameshift mutations induce hyperexcitability in trigeminal ganglion neurons. Using CRISPR-Cas9 engineering to correct the F139WfsX24 mutation in induced pluripotent stem cellbased models, a reversal of the neuronal excitability phenotype was demonstrated [76].…”

Section: Other Genes Implicated In Migraine With Aura Syndromes?mentioning

confidence: 99%

Genetics of migraine aura: an update

2020

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Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura.

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A causal role for TRESK loss of function in migraine mechanisms

Cited by 53 publications

References 38 publications

The Background K+ Channel TRESK in Sensory Physiology and Pain

The Background K+ Channel TRESK in Sensory Physiology and Pain

TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses

Genetics of migraine aura: an update

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