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A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome

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      Summary

      Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12–8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans.

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      Highlights

      ► We describe a novel human autosomal-dominant pain syndrome (FEPS) ► We demonstrate linkage of FEPS to a TRPA1 N855S point mutation ► FEPS patients show debilitating pain on fasting and physical stress ► N855S TRPA1 channels show enhanced inward currents but unaltered pharmacology

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      Most cited references 57

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      TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.

      TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.
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        Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.

        Wasabi, horseradish and mustard owe their pungency to isothiocyanate compounds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mechanical stimuli. Despite their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors.
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          Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.

          Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.
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            Author and article information

            Affiliations
            [1 ]Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK
            [2 ]Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK
            [3 ]Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
            [4 ]Grupo de Neurociencias, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
            [5 ]Grupo de Mapeo Genético, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
            [6 ]Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK
            [7 ]Department of Neurorestoration, Wolfson CARD, Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL, UK
            [8 ]World Class University Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Korea
            Author notes
            []Corresponding author j.wood@ 123456ucl.ac.uk
            [∗∗ ]Corresponding author a.ruizlin@ 123456ucl.ac.uk
            [9]

            These authors contributed equally to this work

            Contributors
            Journal
            Neuron
            Neuron
            Neuron
            Cell Press
            0896-6273
            1097-4199
            10 June 2010
            10 June 2010
            : 66
            : 5
            : 671-680
            20547126 4769261 S0896-6273(10)00323-5 10.1016/j.neuron.2010.04.030
            © 2010 The Authors. Published by Elsevier Inc.

            This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

            Categories
            Clinical Study

            Neurosciences

            molneuro, humdisease, signaling

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