TRPA1 Contributes to Cold Hypersensitivity

Camino, Donato del; Murphy, Sarah; Heiry, Melissa; Barrett, Lee; Earley, Taryn J.; Cook, Colby A.; Petrus, Matt; Zhao, Michael; D'Amours, Marc; Deering, Nate; Brenner, Gary J.; Costigan, Michael; Hayward, Neil J.; Chong, Jayhong A.; Fanger, Christopher M.; Woolf, Clifford J.; Patapoutian, Ardem; Moran, Magdalene M.

doi:10.1523/jneurosci.2580-10.2010

Cited by 253 publications

(245 citation statements)

References 39 publications

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“…Mammalian TRPA1 has been suggested to function as a cold-activated channel (41,42); thus, one could argue that we have interchanged properties between two thermally sensitive channel orthologs, albeit in opposite directions (cold-sensitive vs. heat-sensitive). However, under our experimental conditions, oocytes expressing human TRPA1 showed no cold-evoked currents with cooling down to 10-12°C, consistent with recent reports that cold produces slight or no activation of transfected cells or sensory neurons expressing TRPA1 (43,44). Aminoterminal ARs represent a structural hallmark of many members of the extended family of TRP channels, but their functional roles remain largely unknown.…”

Section: Discussionsupporting

confidence: 91%

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cordero-Morales¹,

Gracheva²,

Julius

2011

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

195

188

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Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide array of physical and chemical stimuli, making them important components of sensory systems in both vertebrate and invertebrate organisms. Mammalian TRPA1 channels are activated by chemically reactive irritants, whereas snake and Drosophila TRPA1 orthologs are preferentially activated by heat. By comparing human and rattlesnake TRPA1 channels, we have identified two portable heat-sensitive modules within the ankyrin repeat-rich aminoterminal cytoplasmic domain of the snake ortholog. Chimeric channel studies further demonstrate that sensitivity to chemical stimuli and modulation by intracellular calcium also localize to the N-terminal ankyrin repeat-rich domain, identifying this region as an integrator of diverse physiological signals that regulate sensory neuron excitability. These findings provide a framework for understanding how restricted changes in TRPA1 sequence account for evolution of physiologically diverse channels, also identifying portable modules that specify thermosensitivity.chemosensation | pain | thermosensation | calcium modulation | somatosensation P rimary afferent (somatosensory) neurons detect a range of physical and chemical stimuli, including temperature, pressure, and noxious irritants (1). The transient receptor potential (TRP) channel family has been shown to play a predominant role in these processes, particularly in regard to thermosensitivity and chemosensitivity (2-5). TRPA1, otherwise known as the "wasabi receptor," plays a key role in somatosensation in evolutionarily diverse phyla, including vertebrate and invertebrate species. Mammalian TRPA1 is expressed by primary afferent sensory neurons of the pain pathway, where it functions as a sensor of environmental and endogenous chemical irritants, such as allyl isothiocyanate (AITC), acrolein, and 4-hydroxynonena, and contributes to cellular mechanisms underlying inflammatory pain (6-9).TRPA1 channels show species-specific functional variation to suit their physiological roles. For example, snakes are unique among vertebrates in that their TRPA1 channels are heat-sensitive, which some species (rattlesnakes, boas, and pythons) have exploited to detect infrared radiation (10). Similarly, insect TRPA1 channels are heat-sensitive and contribute to thermal avoidance behaviors (11)(12)(13)(14). In these cases, however, thermosensitivity comes at the expense of chemosensitivity, such that AITC and other chemical irritants still activate these channels but with reduced potency compared with mammalian orthologs (10). Despite clear physiological differences between snake and mammalian TRPA1 channels, they share significant amino acid identity (56%), providing a unique opportunity to exploit sequence comparisons and domain swaps to pinpoint structural elements associated with stimulus detection and/or gating. Delineating elements that contribute to TRPA1 function will provide insights into the evolutionary process whereby structural changes lead t...

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Section: Discussionsupporting

confidence: 91%

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cordero-Morales¹,

Gracheva²,

Julius

2011

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

195

188

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“…In addition, three of 11 C-MH fibers developed de novo cold responsiveness after MG application and then showed a mean cold threshold of 22.4 Ϯ 3°C and a mean cold response of 15 Ϯ 7.4 spikes/stimulus, which is similar to the cold responsiveness of C-MHC fibers (15 Ϯ 3 spikes/stimulus). These conspicuous findings on cold sensitivity may provide at least some circumstantial evidence for MG-induced hypersensitivity of skin nerve termini to cooling that would correspond to the established role of TRPA1 in various animal models of cold hyperalgesia (50).…”

Section: Mg Differentially Activates Subtypes Of Cutaneous Afferents mentioning

confidence: 70%

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

Eberhardt

Filipovic

Leffler

et al. 2012

Journal of Biological Chemistry

177

174

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Background: Methylglyoxal is a reactive metabolite that modifies proteins and accumulates in diabetes and uremia. Results: Methylglyoxal excites nociceptors and releases neuropeptides via activation of TRPA1 channels by modifying their intracellular N-terminal cysteine and lysine residues. Conclusion: Methylglyoxal acting through TRPA1 is a possible cause of painful metabolic neuropathies. Significance: Methylglyoxal and its reaction with TRPA1 are promising targets for medicinal chemistry to fight neurotoxicity.

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“…Heat can enhance agonistinduced desensitization not only in heat-gated channels but also in cold-gated channels. The activity of mammalian TRPA1 is enhanced by cold temperature (45). When mammalian TRPA1 is activated by chemical agonists, the rate and extent of desensitization is enhanced as the ambient temperature increases (46).…”

Section: Discussionmentioning

confidence: 99%

Carboxyl-terminal Domain of Transient Receptor Potential Vanilloid 1 Contains Distinct Segments Differentially Involved in Capsaicin- and Heat-induced Desensitization

Joseph

Wang

Lee

et al. 2013

Journal of Biological Chemistry

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Background: Mechanisms of TRPV1 desensitization by heat are not fully understood. Results: Distinct segments of the TRPV1 carboxyl-terminal domain are differentially involved in capsaicin-and heat-induced desensitization. Conclusion: Capsaicin and heat desensitizes TRPV1 through a distinct structural basis. Significances: Selective enhancement of desensitization could be a novel strategy for suppressing heat hyperalgesia.

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TRPA1 Contributes to Cold Hypersensitivity

Cited by 253 publications

References 39 publications

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

Carboxyl-terminal Domain of Transient Receptor Potential Vanilloid 1 Contains Distinct Segments Differentially Involved in Capsaicin- and Heat-induced Desensitization

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