TRPA1: a molecular view

Meents, Jannis; Ciotu, Cosmin I; Fischer, Michael J.M.

doi:10.1152/jn.00524.2018

Cited by 115 publications

(100 citation statements)

References 167 publications

(201 reference statements)

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“…Our current data furthermore demonstrate that TRPA1 is an important signaling factor in colitis-associated hyperalgesia at the primary sensory neuron level because the severity of colitis was not affected by TRPA1 blockade or deletion. This ion channel is abundantly expressed in a subpopulation of DRG and TG sensory neurons and thought to be an important nocisensor ion channel, given that it is activated by mechanical and chemical pain stimuli 15,16,31 . The current findings underpin this contention as they show that TRPA1 plays an essential mediator role in the somatic mechanical hyperalgesia associated with DSS-induced colonic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis

Jain

Materazzi

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et al. 2020

Sci Rep

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Pain evoked by visceral inflammation is often 'referred' to the somatic level. Transient receptor potential ankyrin 1 (TRPA1) has been reported to contribute to visceral pain-like behavior in dextran sulfate sodium (DSS)-evoked colitis. However, the role of TRPA1 in somatic component of hypersensitivity due to visceral inflammation is unknown. The present study investigated the role of TRPA1 in colitis-evoked mechanical hypersensitivity at the somatic level. Colitis was induced in mice by adding DSS to drinking water for one week. Control and DSS-treated mice were tested for various parameters of colitis as well as mechanical pain sensitivity in abdominal and facial regions. DSS treatment caused mechanical hypersensitivity in the abdominal and facial skin. Pharmacological blockade or genetic deletion of TRPA1 prevented the colitis-associated mechanical hypersensitivity in the abdominal and facial skin areas although the severity of colitis remained unaltered. DSS treatment increased expression of TRPA1 mRNA in cultured dorsal root ganglion (DRG) neurons, but not trigeminal ganglion neurons, and selectively enhanced currents evoked by the TRPA1 agonist, allyl isothiocyanate, in cultured DRG neurons. Our findings indicate that the TRPA1 channel contributes to colitis-associated mechanical hypersensitivity in somatic tissues, an effect associated with upregulation of TRPA1 expression and responsiveness in DRG nociceptors.

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Section: Discussionmentioning

confidence: 99%

Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis

Jain

Materazzi

Logu

et al. 2020

Sci Rep

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“…Many of these compounds are thiol-reactive electrophiles that activate the channel by covalent modification of the channel. Others are non-reactive, and they activate the channel by binding without covalent modifications [145].…”

Section: Trpa1mentioning

confidence: 99%

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

Islam

2020

Cells

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Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines.

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“…A large number (>150) of single-point mutations and chimeras of human TRPA1 have been functionally characterized in the literature (Meents et al, 2019), yet the published data do not enable us to fully understand the molecular details of the channel function, mostly because (1) the available structures of TRPA1 capture the channel in an intermediate or inactivated conformation (Paulsen et al, 2015;Suo et al, 2020) which does not allow to distinguish the functional states, (2) the structures lack information on a considerable (∼50%) part of the protein, (3) the impact of the interactions of TRPA1 with various important endogenous proteins and cellular signaling mechanisms has not yet been fully characterized (Zygmunt and Hogestatt, 2014;Gouin et al, 2017;Talavera et al, 2019), and (4) the extent to which TRPA1 can be regulated by its membrane environment is still only gradually being uncovered (Hirono et al, 2004;Akopian et al, 2007;Dai et al, 2007;Karashima et al, 2008;Witschas et al, 2015;Macikova et al, 2019;Startek et al, 2019). Obviously, a better understanding of all these issues is key for a precise description of the mechanisms of TRPA1 activation, and, perhaps more importantly, for rational screening of its novel modulators as potential therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Proximal C-Terminus Serves as a Signaling Hub for TRPA1 Channel Regulation via Its Interacting Molecules and Supramolecular Complexes

et al. 2020

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Our understanding of the general principles of the polymodal regulation of transient receptor potential (TRP) ion channels has grown impressively in recent years as a result of intense efforts in protein structure determination by cryo-electron microscopy. In particular, the high-resolution structures of various TRP channels captured in different conformations, a number of them determined in a membrane mimetic environment, have yielded valuable insights into their architecture, gating properties and the sites of their interactions with annular and regulatory lipids. The correct repertoire of these channels is, however, organized by supramolecular complexes that involve the localization of signaling proteins to sites of action, ensuring the specificity and speed of signal transduction events. As such, TRP ankyrin 1 (TRPA1), a major player involved in various pain conditions, localizes into cholesterol-rich sensory membrane microdomains, physically interacts with calmodulin, associates with the scaffolding A-kinase anchoring protein (AKAP) and forms functional complexes with the related TRPV1 channel. This perspective will contextualize the recent biochemical and functional studies with emerging structural data with the aim of enabling a more thorough interpretation of the results, which may ultimately help to understand the roles of TRPA1 under various physiological and pathophysiological pain conditions. We demonstrate that an alteration to the putative lipid-binding site containing a residue polymorphism associated with human asthma affects the cold sensitivity of TRPA1. Moreover, we present evidence that TRPA1 can interact with AKAP to prime the channel for opening. The structural bases underlying these interactions remain unclear and are definitely worth the attention of future studies.

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TRPA1: a molecular view

Cited by 115 publications

References 167 publications

Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis

Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

Proximal C-Terminus Serves as a Signaling Hub for TRPA1 Channel Regulation via Its Interacting Molecules and Supramolecular Complexes

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