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TRPA1 is a chemosensory ion channel that functions as a sentinel for structurally diverse electrophilic irritants. Channel activation occurs through an unusual mechanism involving covalent modification of cysteine residues clustered within an amino-terminal cytoplasmic domain. Here, we describe a peptidergic scorpion toxin (WaTx) that activates TRPA1 by penetrating the plasma membrane to access the same intracellular site modified by reactive electrophiles. WaTx stabilizes TRPA1 in a biophysically distinct active state characterized by prolonged channel openings and low Ca2+ permeability. Consequently, WaTx elicits acute pain and pain hypersensitivity but fails to trigger efferent release of neuropeptides and neurogenic inflammation typically produced by noxious electrophiles. These findings provide a striking example of convergent evolution whereby chemically disparate animal- and plant-derived irritants target the same key allosteric regulatory site to differentially modulate channel activity. WaTx is a unique pharmacological probe for dissecting TRPA1 function and its contribution to acute and persistent pain.

Atopic dermatitis (AD) is the most common skin disease in children. It is characterized by relapsing inflammation, skin-barrier defects, and intractable itch. However, the pathophysiology of itch in AD remains enigmatic. Here, we examine the contribution of Tmem79, an orphan transmembrane protein linked to AD in both mice and humans. We show that Tmem79 is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic Tmem79 is sufficient to elicit robust scratching. Tmem79-/- mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79-/- mice, mast cell degranulation produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve activation of TRPV1- afferents. TMEM79 has limited sequence homology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging reactive species, and may thus play a role in regulating oxidative stress. In any case, mechanistic insights from this model suggest that therapeutics targeting PGE2 and/or H1R/H4R histaminergic signaling pathways may represent useful avenues to treat Tmem79-associated AD itch. Our findings suggest that individuals with mutations in Tmem79 develop AD due to the loss of protection from oxidative stress.

Voltage-gated sodium (Na.sub.v) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Na.sub.v channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate the Na.sub.v1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na.sub.v1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Na.sub.v1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na.sub.v1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain. Two spider toxins are shown to target the Na.sub.v1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling. Na.sub.v1.1 channels mediate mechanical pain Mutations affecting several Na.sub.v1 subtype voltage-gated sodium channels have been shown to be associated with insensitivity to pain or persistent pain syndromes. Na.sub.v1.1 is expressed by somatosensory neurons, but no direct link has been established between this subtype and nociception. Further studies have been hampered by a paucity of pharmacological agents that discriminate between the closely related members of the Na.sub.v1 family. Now David Julius and colleagues have identified two spider toxins specifically targeting Na.sub.v1.1, and use them to show that this channel is key to the specific transduction of mechanical but not thermal pain by myelinated A[delta] sensory fibres. Previous genetic studies of Na.sub.v1.1 indicate that such selective agents may open therapeutic avenues in disorders associated with the central nervous system, such as epilepsy, autism and Alzheimer disease. The involvement of Na.sub.v1.1 channels in mediating mechanical pain reported here was unexpected., Author(s): Jeremiah D. Osteen [sup.1] , Volker Herzig [sup.2] , John Gilchrist [sup.3] , Joshua J. Emrick [sup.1] , Chuchu Zhang [sup.1] , Xidao Wang [sup.4] , Joel Castro [sup.5] [...]

Pain is the anticipated output of the trigeminal sensory neurons that innervate the tooth's vital interior 1,2 ; however, the contribution of intradental neurons to healthy tooth sensation has yet to be defined. Here, we employ in vivo Ca 2+ imaging to identify and define a population of myelinated high-threshold mechanoreceptors (intradental HTMRs) that detect superficial structural damage of the tooth and initiate jaw opening to protect teeth from damage. Intradental HTMRs remain inactive when direct forces are applied to the intact tooth but become responsive to forces when the structural integrity of the tooth is compromised, and the dentin or pulp is exposed. Their terminals collectively innervate the inner dentin through overlapping receptive fields, allowing them to monitor the superficial structures of the tooth. Indeed, intradental HTMRs detect superficial enamel damage and encode its degree, and their responses persist in the absence of either PIEZO2 or Na v 1.8 3,4 . Optogenetic activation of intradental HTMRs triggers a rapid, jaw opening reflex via contraction of the digastric muscle. Taken together, our data indicate that intradental HTMRs serve as sentinels that guard against mechanical threats to the tooth, and their activation results in physical tooth separation to minimize irreversible structural damage. Our work provides a new perspective on the role of intradental neurons as protective rather than exclusively pain-inducing and illustrates additional diversity in the functions of interoreceptors.