Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

Morenilla‐Palao, Cruz; Luis, Enoch; Fernández‐Peña, Carlos; Quintero, Eva; Weaver, Janelle L.; Bayliss, Douglas A.; Viana, Félix

doi:10.1016/j.celrep.2014.08.003

Cited by 87 publications

(87 citation statements)

References 71 publications

(126 reference statements)

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“…Although TASK3 channels have low overall levels of expression in DRG neurons and there is little evidence to show a role for them in general pain transduction, a recent study has suggested that these channels are highly enriched in TRPM8 positive neurons [72]. Since TASK3 knockout mice were found to have a hypersensitivity to cold stimuli, this suggests that TASK3 channels may have an important role in the transduction of painful cold stimuli [72].…”

Section: Twik1 and Task3 Channelsmentioning

confidence: 96%

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

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

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Section: Twik1 and Task3 Channelsmentioning

confidence: 96%

“…Since TASK3 knockout mice were found to have a hypersensitivity to cold stimuli, this suggests that TASK3 channels may have an important role in the transduction of painful cold stimuli [72].…”

Section: Twik1 and Task3 Channelsmentioning

confidence: 99%

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

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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“…For example, two-pore, nongated potassium channels contribute to cold pain as they are down-regulated after oxaliplatin treatment, thereby leading to enhanced neuronal excitability (61,62). Moreover, antagonism of the voltage-gated sodium channel Nav1.6 attenuated neuropathic cold allodynia (63).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin-GFRα3 signaling can be targeted to selectively treat cold pain.W hen pain continues past its usefulness as a warning of potential tissue damage, it becomes a debilitating condition for which few viable treatments are currently available. The result can be an exacerbation of pain in response to both innocuous (allodynia) and noxious (hyperalgesia) stimuli (1). For example, pain felt with normally pleasant mild cooling (cold allodynia) occurs in many pathological conditions, such as fibromyalgia, multiple sclerosis, stroke, and chemotherapeutic-induced polyneuropathy, but what underlies this specific form of pain at the cellular or molecular level is largely unknown (2-5). Pain-sensing afferent neurons (nociceptors) are sensitized during injury or disease, in part, by a vast array of proalgesic compounds termed the "inflammatory soup" (e.g., neurotrophic factors, protons, bradykinin, prostaglandins, and ATP) (1). These substances are released locally at the site of injury by infiltrating immune cells, such as macrophages, neutrophils, and T cells, as well as resident cells, including keratinocytes and mast cells (6), and either directly activate sensory receptors or sensitize them to subsequent stimuli (7). Moreover, prolonged inflammation can lead to central sensitization (in the spinal cord and brain) and bring about long-lasting chronic pain that persists after acute inflammation has resolved. Thus, a better understanding of the molecules involved in neuroinflammation may lead to therapeutic options for acute and chronic pain.Of the range of proalgesics known to promote pain, only nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor family ligand (GFL) artemin have been shown to lead to cold hypersensitivity (8-11). Both are major components of the inflammatory soup and produce nociceptor sensitization and pain through their cognate cell surface rece...

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“…A range of potassium channels, including the two-pore domain (2PK) background channels TRAAK, TASK-3, TREK-1, TRESK [118,119] as well as voltage-gated potassium channels K v 1 and K v 7.2/7.3, have been implicated in the physiology of cold sensing and the pathophysiology of cold pain. Closure of background 2PK channels underpins cooling-induced increase in excitability of cultured DRG neurons, leading to membrane depolarisation and increased firing [120,121].…”

Section: Potassium Channelsmentioning

confidence: 99%

Therapeutic opportunities for targeting cold pain pathways

Yin

Zimmermann

Vetter

et al. 2015

Biochemical Pharmacology

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Please cite this article as: Yin K, Zimmermann K, Vetter I, Lewis RJ, Therapeutic opportunities for targeting cold pain pathways, Biochemical Pharmacology (2014), http://dx.doi. org/10.1016/j.bcp.2014.09.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

Cited by 87 publications

References 71 publications

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

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

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

Therapeutic opportunities for targeting cold pain pathways

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