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

Royal, Perrine; Andrés‐Bilbé, Alba; Prado, Pablo Ávalos; Verkest, Clément; Wdziekonski, Brigitte; Schaub, Sébastien; Baron, Anne; Lesage, Florian; Gasull, Xavier; Levitz, Joshua; Sandoz, Guillaume

doi:10.1016/j.neuron.2018.11.039

Cited by 113 publications

(144 citation statements)

References 44 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…TRESK's main role has been attributed to preventing neuronal depolarization , and reduction of its expression after nerve injury or inflammation contribute to neuronal hyperexcitability (Dobler et al 2007;Tulleuda et al 2011;Marsh et al 2012). Mutations in this channel have been linked to the enhanced nociceptor excitability that occurs during familial migraine with aura (Lafrenière et al 2010;Royal et al 2019). Here, we propose that TRESK balances the effects of depolarizing stimuli, acting as a brake to prevent the activation of specific subpopulations of sensory neurons.…”

Section: Discussionmentioning

confidence: 95%

“…; Royal et al . ). Here, we propose that TRESK balances the effects of depolarizing stimuli, acting as a brake to prevent the activation of specific subpopulations of sensory neurons.…”

Section: Discussionmentioning

confidence: 97%

“…Likewise, trigeminal expression of a mutated form of TRESK linked to migraine results in facial mechanical allodynia (Royal et al . ). Other studies have also reported an increase in innocuous touch sensitivity in mice after TRESK deletion, although they did not find a significant difference in punctate mechanical sensitivity (Weir et al .…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, a frameshift mutation leading to the truncation of the channel has been associated with familial migraine with aura, thus involving TRESK in the enhanced activation of the trigeminovascular system and the release of inflammatory neuropeptides in the meninges and cerebral vessels triggering migraine pain (Lafrenière et al 2010). This is supported by a recent study demonstrating that mutant TRESK can heteromerize with TREK-1/2 to decrease their function and trigger migraine pain (Royal et al 2019).…”

Section: Introductionmentioning

confidence: 92%

“…This is supported by a recent study demonstrating that mutant TRESK can heteromerize with TREK‐1/2 to decrease their function and trigger migraine pain (Royal et al . ).…”

Section: Introductionmentioning

confidence: 97%

See 4 more Smart Citations

TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

Castellanos

Pujol-Coma

Andrés‐Bilbé

et al. 2020

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key points TRESK background K+ channel is expressed in sensory neurons and acts as a brake to reduce neuronal activation. Deletion of the channel enhances the excitability of nociceptors. Skin nociceptive C‐fibres show an enhanced activation by cold and mechanical stimulation in TRESK knockout animals. Channel deletion selectively enhances mechanical and cold sensitivity in mice, without altering sensitivity to heat. These results indicate that the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold‐sensing. Abstract Background potassium‐permeable ion channels play a critical role in tuning the excitability of nociceptors, yet the precise role played by different subsets of channels is not fully understood. Decreases in TRESK (TWIK‐related spinal cord K+ channel) expression/function enhance excitability of sensory neurons, but its role in somatosensory perception and nociception is poorly understood. Here, we used a TRESK knockout (KO) mouse to address these questions. We show that TRESK regulates the sensitivity of sensory neurons in a modality‐specific manner, contributing to mechanical and cold sensitivity but without any effect on heat sensitivity. Nociceptive neurons isolated from TRESK KO mice show a decreased threshold for activation and skin nociceptive C‐fibres show an enhanced activation by cold and mechanical stimulation that was also observed in behavioural tests in vivo. TRESK is also involved in osmotic pain and in early phases of formalin‐induced inflammatory pain, but not in the development of mechanical and heat hyperalgesia during chronic pain. In contrast, mice lacking TRESK present cold allodynia that is not further enhanced by oxaliplatin. In summary, genetic removal of TRESK uncovers enhanced mechanical and cold sensitivity, indicating that the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold‐sensing, acting as a brake to prevent activation by innocuous stimuli.

show abstract

Section: Discussionmentioning

confidence: 95%

“…; Royal et al . ). Here, we propose that TRESK balances the effects of depolarizing stimuli, acting as a brake to prevent the activation of specific subpopulations of sensory neurons.…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 92%

“…This is supported by a recent study demonstrating that mutant TRESK can heteromerize with TREK‐1/2 to decrease their function and trigger migraine pain (Royal et al . ).…”

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

Castellanos

Pujol-Coma

Andrés‐Bilbé

et al. 2020

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Sun,

Yang,

Wang

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high‐energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two‐pore‐domain K+ channel (K2P) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin‐mediated TREK1/2 pathway may provide a therapeutic approach for ameliorating PDNP.

show abstract

Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

Kim,

Van,

Nam

et al. 2024

ChemMedChem

View full text Add to dashboard Cite

TWIK‐related K(+) channel (TREK)‐2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK‐2 is of significance for the development of new analgesics. Recent studies have shown that α‐Mangostin (α‐MG) activates TREK‐2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK‐2, α‐MG is also observed to share the same binding site with NFx, and this implies that TREK‐2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK‐2 is activated by α‐MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α‐MG and NFx exhibit opposing effects at the same binding site of TREK‐2. These findings will broaden our understanding of TREK‐2 modulation, providing clues for designing novel analgesic drugs.

show abstract

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

Cited by 113 publications

References 44 publications

TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

Contact Info

Product

Resources

About

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

Cited by 113 publications

References 44 publications

TRESK background K+ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

TRESK background K+ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

Contact Info

Product

Resources

About

TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

TRESK background K⁺ channel deletion selectively uncovers enhanced mechanical and cold sensitivity