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.

Department of Cellular Neurophysiology Institute of Physiology The Czech Academy of Sciences Prague Czechia

Department of Physical and Macromolecular Chemistry Faculty of Science Charles University Prague Czechia

Department of Physiology Faculty of Science Charles University Prague Czechia

Division of Biomolecular Physics Faculty of Mathematics and Physics Institute of Physics Charles University Prague Czechia

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Akopian A. N. (2011). Regulation of nociceptive transmission at the periphery via TRPA1-TRPV1 interactions. Curr. Pharm. Biotechnol. 12 89–94. 10.2174/138920111793937952 PubMed DOI

Akopian A. N., Ruparel N. B., Jeske N. A., Hargreaves K. M. (2007). Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. J. Physiol. 583(Pt 1), 175–193. 10.1113/jphysiol.2007.133231 PubMed DOI PMC

Andrade E. L., Meotti F. C., Calixto J. B. (2012). TRPA1 antagonists as potential analgesic drugs. Pharmacol. Ther. 133 189–204. 10.1016/j.pharmthera.2011.10.008 PubMed DOI

Bandell M., Story G. M., Hwang S. W., Viswanath V., Eid S. R., Petrus M. J., et al. (2004). Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41 849–857. 10.1016/s0896-6273(04)00150-3 PubMed DOI

Bautista D. M., Jordt S. E., Nikai T., Tsuruda P. R., Read A. J., Poblete J., et al. (2006). TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124 1269–1282. 10.1016/j.cell.2006.02.023 PubMed DOI

Brackley A. D., Gomez R., Guerrero K. A., Akopian A. N., Glucksman M. J., Du J., et al. (2017). A-Kinase anchoring protein 79/150 scaffolds transient receptor potential A 1 phosphorylation and sensitization by metabotropic glutamate receptor activation. Sci. Rep. 7:1842. 10.1038/s41598-017-01999-4 PubMed DOI PMC

Cao E., Liao M., Cheng Y., Julius D. (2013). TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504 113–118. 10.1038/nature12823 PubMed DOI PMC

Cavanaugh E. J., Simkin D., Kim D. (2008). Activation of transient receptor potential A1 channels by mustard oil, tetrahydrocannabinol and Ca(2+) reveals different functional channel states. Neuroscience 154 1467–1476. 10.1016/j.neuroscience.2008.04.048 PubMed DOI

Chen J., Hackos D. H. (2015). TRPA1 as a drug target–promise and challenges. Naunyn Schmiedeberg’s Arch. Pharmacol. 388 451–463. 10.1007/s00210-015-1088-3 PubMed DOI PMC

Chen J., Kang D., Xu J., Lake M., Hogan J. O., Sun C., et al. (2013). Species differences and molecular determinant of TRPA1 cold sensitivity. Nat. Commun. 4:2501. 10.1038/ncomms3501 PubMed DOI PMC

Cordero-Morales J. F., Gracheva E. O., Julius D. (2011). Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli. Proc. Natl. Acad. Sci. USA. 108 E1184–E1191. 10.1073/pnas.1114124108 PubMed DOI PMC

Dai Y., Wang S., Tominaga M., Yamamoto S., Fukuoka T., Higashi T., et al. (2007). Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J. Clin. Invest. 117 1979–1987. 10.1172/jci30951 PubMed DOI PMC

De Logu F., Nassini R., Materazzi S., Carvalho Goncalves M., Nosi D., Rossi Degl’Innocenti D., et al. (2017). Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice. Nat. Commun. 8:1887. 10.1038/s41467-017-01739-2 PubMed DOI PMC

Deering-Rice C. E., Shapiro D., Romero E. G., Stockmann C., Bevans T. S., Phan Q. M., et al. (2015). Activation of transient receptor potential ankyrin-1 by insoluble particulate material and association with asthma. Am. J. Respir. Cell Mol. Biol. 53 893–901. 10.1165/rcmb.2015-0086OC PubMed DOI PMC

del Camino D., Murphy S., Heiry M., Barrett L. B., Earley T. J., Cook C. A., et al. (2010). TRPA1 contributes to cold hypersensitivity. J. Neurosci. 30 15165–15174. 10.1523/JNEUROSCI.2580-10.2010 PubMed DOI PMC

Dittert I., Benedikt J., Vyklicky L., Zimmermann K., Reeh P. W., Vlachova V. (2006). Improved superfusion technique for rapid cooling or heating of cultured cells under patch-clamp conditions. J. Neurosci. Methods 151 178–185. 10.1016/j.jneumeth.2005.07.005 PubMed DOI

Doerner J. F., Gisselmann G., Hatt H., Wetzel C. H. (2007). Transient receptor potential channel A1 is directly gated by calcium ions. J. Biol. Chem. 282 13180–13189. 10.1074/jbc.m607849200 PubMed DOI

El Karim I. A., Linden G. J., Curtis T. M., About I., McGahon M. K., Irwin C. R., et al. (2011). Human dental pulp fibroblasts express the “cold-sensing” transient receptor potential channels TRPA1 and TRPM8. J. Endod. 37 473–478. 10.1016/j.joen.2010.12.017 PubMed DOI

Faux M. C., Scott J. D. (1997). Regulation of the AKAP79-protein kinase C interaction by Ca2+/Calmodulin. J. Biol. Chem. 272 17038–17044. 10.1074/jbc.272.27.17038 PubMed DOI

Fischer M. J., Balasuriya D., Jeggle P., Goetze T. A., McNaughton P. A., Reeh P. W., et al. (2014). Direct evidence for functional TRPV1/TRPA1 heteromers. Pflugers Arch. 466 2229–2241. 10.1007/s00424-014-1497-z PubMed DOI

Gallo V., Dijk F. N., Holloway J. W., Ring S. M., Koppelman G. H., Postma D. S., et al. (2017). TRPA1 gene polymorphisms and childhood asthma. Pediatr.Allergy Immunol. 28 191–198. 10.1111/pai.12673 PubMed DOI PMC

Gouin O., L’Herondelle K., Lebonvallet N., Le Gall-Ianotto C., Sakka M., Buhe V., et al. (2017). TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 8 644–661. 10.1007/s13238-017-0395-5 PubMed DOI PMC

Hall B. E., Prochazkova M., Sapio M. R., Minetos P., Kurochkina N., Binukumar B. K., et al. (2018). Phosphorylation of the transient receptor potential ankyrin 1 by Cyclin-dependent Kinase 5 affects Chemo-nociception. Sci. Rep. 8:1177. 10.1038/s41598-018-19532-6 PubMed DOI PMC

Hasan R., Leeson-Payne A. T., Jaggar J. H., Zhang X. (2017). Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 Channels. Sci. Rep. 7:45098. 10.1038/srep45098 PubMed DOI PMC

Hirono M., Denis C. S., Richardson G. P., Gillespie P. G. (2004). Hair cells require phosphatidylinositol 4,5-bisphosphate for mechanical transduction and adaptation. Neuron 44 309–320. 10.1016/j.neuron.2004.09.020 PubMed DOI

Hoffmann T., Kistner K., Miermeister F., Winkelmann R., Wittmann J., Fischer M. J., et al. (2013). TRPA1 and TRPV1 are differentially involved in heat nociception of mice. Eur. J. f Pain 17 1472–1482. 10.1002/j.1532-2149.2013.00331.x PubMed DOI

Hossain M. I., Iwasaki H., Okochi Y., Chahine M., Higashijima S., Nagayama K., et al. (2008). Enzyme domain affects the movement of the voltage sensor in ascidian and zebrafish voltage-sensing phosphatases. J. Biol. Chem. 283 18248–18259. 10.1074/jbc.M706184200 PubMed DOI

Humphrey W., Dalke A., Schulten K. (1996). VMD: visual molecular dynamics. J. Mol. Graph. 14 33–38. 10.1016/0263-7855(96)00018-5 PubMed DOI

Hynkova A., Marsakova L., Vaskova J., Vlachova V. (2016). N-terminal tetrapeptide T/SPLH motifs contribute to multimodal activation of human TRPA1 channel. Sci. Rep. 6:28700. 10.1038/srep28700 PubMed DOI PMC

Ishida H., Vogel H. J. (2006). Protein-peptide interaction studies demonstrate the versatility of calmodulin target protein binding. Protein Peptide Lett. 13 455–465. 10.2174/092986606776819600 PubMed DOI

Jaquemar D., Schenker T., Trueb B. (1999). An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts. J. Biol. Chem. 274 7325–7333. 10.1074/jbc.274.11.7325 PubMed DOI

Jordt S. E., Bautista D. M., Chuang H. H., McKemy D. D., Zygmunt P. M., Hogestatt E. D., et al. (2004). Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427 260–265. 10.1038/nature02282 PubMed DOI

Kadkova A., Synytsya V., Krusek J., Zimova L., Vlachova V. (2017). Molecular basis of TRPA1 regulation in nociceptive neurons. A Review. Physiol. Res. 66 425–439. 10.33549/physiolres.933553 PubMed DOI

Karashima Y., Prenen J., Meseguer V., Owsianik G., Voets T., Nilius B. (2008). Modulation of the transient receptor potential channel TRPA1 by phosphatidylinositol 4,5-biphosphate manipulators. Pflugers Arch. 457 77–89. 10.1007/s00424-008-0493-6 PubMed DOI

Karashima Y., Talavera K., Everaerts W., Janssens A., Kwan K. Y., Vennekens R., et al. (2009). TRPA1 acts as a cold sensor in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 106 1273–1278. 10.1073/pnas.0808487106 PubMed DOI PMC

Knowlton W. M., Bifolck-Fisher A., Bautista D. M., McKemy D. D. (2010). TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Pain 150 340–350. 10.1016/j.pain.2010.05.021 PubMed DOI PMC

Koivisto A., Jalava N., Bratty R., Pertovaara A. (2018). TRPA1 Antagonists for Pain Relief. Pharmaceuticals 11:E117. 10.3390/ph11040117 PubMed DOI PMC

Kremeyer B., Lopera F., Cox J. J., Momin A., Rugiero F., Marsh S., et al. (2010). A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 66 671–680. 10.1016/j.neuron.2010.04.030 PubMed DOI PMC

Kwan K. Y., Allchorne A. J., Vollrath M. A., Christensen A. P., Zhang D. S., Woolf C. J., et al. (2006). TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50 277–289. 10.1016/j.neuron.2006.03.042 PubMed DOI

Kwan K. Y., Glazer J. M., Corey D. P., Rice F. L., Stucky C. L. (2009). TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J. Neurosci. 29 4808–4819. 10.1523/JNEUROSCI.5380-08.2009 PubMed DOI PMC

Lau S. Y., Procko E., Gaudet R. (2012). Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. J. Gen. Physiol. 140 541–555. 10.1085/jgp.201210810 PubMed DOI PMC

Macikova L., Sinica V., Kadkova A., Villette S., Ciaccafava A., Faherty J., et al. (2019). Putative interaction site for membrane phospholipids controls activation of TRPA1 channel at physiological membrane potentials. FEBS J. 286 3664–3683. 10.1111/febs.14931 PubMed DOI

Meents J. E., Ciotu C. I., Fischer M. J. M. (2019). TRPA1: a molecular view. J. Neurophysiol. 121 427–443. 10.1152/jn.00524.2018 PubMed DOI

Meents J. E., Fischer M. J., McNaughton P. A. (2017). Sensitization of TRPA1 by Protein Kinase A. PloS One 12:e0170097. 10.1371/journal.pone.0170097 PubMed DOI PMC

Melnick C., Kaviany M. (2018). Thermal actuation in TRPV1: role of embedded lipids and intracellular domains. J. Theor. Biol. 444 38–49. 10.1016/j.jtbi.2018.02.004 PubMed DOI

Miyano K., Shiraishi S., Minami K., Sudo Y., Suzuki M., Yokoyama T., et al. (2019). Carboplatin enhances the activity of human transient receptor potential ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways. Int. J. Mo. Sci. 20:E3271. 10.3390/ijms20133271 PubMed DOI PMC

Moparthi L., Kichko T. I., Eberhardt M., Hogestatt E. D., Kjellbom P., Johanson U., et al. (2016). Human TRPA1 is a heat sensor displaying intrinsic U-shaped thermosensitivity. Sci. Rep. 6:28763. 10.1038/srep28763 PubMed DOI PMC

Moparthi L., Survery S., Kreir M., Simonsen C., Kjellbom P., Hogestatt E. D., et al. (2014). Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain. Proc. Natl. Acad. Sci. U.S.A,. 111 16901–16906. 10.1073/pnas.1412689111 PubMed DOI PMC

Mruk K., Farley B. M., Ritacco A. W., Kobertz W. R. (2014). Calmodulation meta-analysis: predicting calmodulin binding via canonical motif clustering. J. Gen. Physiol. 144 105–114. 10.1085/jgp.201311140 PubMed DOI PMC

Nagata K., Duggan A., Kumar G., Garcia-Anoveros J. (2005). Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J. Neurosci. 25 4052–4061. 10.1523/jneurosci.0013-05.2005 PubMed DOI PMC

Okamura Y., Murata Y., Iwasaki H. (2009). Voltage-sensing phosphatase: actions and potentials. J. Physiol. 587 513–520. 10.1113/jphysiol.2008.163097 PubMed DOI PMC

Patel N., Stengel F., Aebersold R., Gold M. G. (2017). Molecular basis of AKAP79 regulation by calmodulin. Nat. Commun. 8:1681. 10.1038/s41467-017-01715-w PubMed DOI PMC

Patil M. J., Salas M., Bialuhin S., Boyd J. T., Jeske N. A., Akopian A. N. (2020). Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association. FASEB J. 34 287–302. 10.1096/fj.201902026R PubMed DOI PMC

Paulsen C. E., Armache J. P., Gao Y., Cheng Y., Julius D. (2015). Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature 520 511–517. 10.1038/nature14367 PubMed DOI PMC

Petho G., Reeh P. W. (2012). Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol. Rev. 92 1699–1775. 10.1152/physrev.00048.2010 PubMed DOI

Pettersen E. F., Goddard T. D., Huang C. C., Couch G. S., Greenblatt D. M., Meng E. C., et al. (2004). UCSF Chimera–a visualization system for exploratory research and analysis. J. Comput. Chem. 25 1605–1612. 10.1002/jcc.20084 PubMed DOI

Rosenbaum T., Gordon-Shaag A., Munari M., Gordon S. E. (2004). Ca2 + /calmodulin modulates TRPV1 activation by capsaicin. J. Gen. Physiol. 123 53–62. 10.1085/jgp.200308906 PubMed DOI PMC

Salas M. M., Hargreaves K. M., Akopian A. N. (2009). TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1. Eur. J. Neurosci. 29 1568–1578. 10.1111/j.1460-9568.2009.06702.x PubMed DOI PMC

Samad A., Sura L., Benedikt J., Ettrich R., Minofar B., Teisinger J., et al. (2011). The C-terminal basic residues contribute to the chemical- and voltage-dependent activation of TRPA1. Biochem. J. 433 197–204. 10.1042/BJ20101256 PubMed DOI PMC

Sawada Y., Hosokawa H., Hori A., Matsumura K., Kobayashi S. (2007). Cold sensitivity of recombinant TRPA1 channels. Brain Res. 1160 39–46. 10.1016/j.brainres.2007.05.047 PubMed DOI

Schmidt M., Dubin A. E., Petrus M. J., Earley T. J., Patapoutian A. (2009). Nociceptive signals induce trafficking of TRPA1 to the plasma membrane. Neuron 64 498–509. 10.1016/j.neuron.2009.09.030 PubMed DOI PMC

Shigetomi E., Tong X., Kwan K. Y., Corey D. P., Khakh B. S. (2011). TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat. Neurosci. 15 70–80. 10.1038/nn.3000 PubMed DOI PMC

Singh A. K., McGoldrick L. L., Demirkhanyan L., Leslie M., Zakharian E., Sobolevsky A. I. (2019). Structural basis of temperature sensation by the TRP channel TRPV3. Nat. Struct. Mol. Biol. 27 221. 10.1038/s41594-019-0318-7 PubMed DOI PMC

Singh A. K., McGoldrick L. L., Sobolevsky A. I. (2018). Structure and gating mechanism of the transient receptor potential channel TRPV3. Nat. Struct. Mol. Biol. 25 805–813. 10.1038/s41594-018-0108-7 PubMed DOI PMC

Sinica V., Zimova L., Barvikova K., Macikova L., Barvik I., Vlachova V. (2019). Human and mouse TRPA1 are heat and cold sensors differentially tuned by voltage. Cells 9:E57. 10.3390/cells9010057 PubMed DOI PMC

Smith F. D., Reichow S. L., Esseltine J. L., Shi D., Langeberg L. K., Scott J. D., et al. (2013). Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. eLife 2:e01319. 10.7554/eLife.01319 PubMed DOI PMC

Startek J. B., Boonen B., Lopez-Requena A., Talavera A., Alpizar Y. A., Ghosh D., et al. (2019). Mouse TRPA1 function and membrane localization are modulated by direct interactions with cholesterol. eLife 8:e46084. 10.7554/eLife.46084 PubMed DOI PMC

Staruschenko A., Jeske N. A., Akopian A. N. (2010). Contribution of TRPV1-TRPA1 interaction to the single channel properties of the TRPA1 channel. J. Biol. Chem. 285 15167–15177. 10.1074/jbc.M110.106153 PubMed DOI PMC

Story G. M., Peier A. M., Reeve A. J., Eid S. R., Mosbacher J., Hricik T. R., et al. (2003). ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112 819–829. 10.1016/s0092-8674(03)00158-2 PubMed DOI

Sulak M. A., Ghosh M., Sinharoy P., Andrei S. R., Damron D. S. (2018). Modulation of TRPA1 channel activity by Cdk5 in sensory neurons. Channels 12 65–75. 10.1080/19336950.2018.1424282 PubMed DOI PMC

Suo Y., Wang Z., Zubcevic L., Hsu A. L., He Q., Borgnia M. J., et al. (2020). Structural insights into Electrophile Irritant Sensing by the human TRPA1 channel. Neuron 105 31009–31008. 10.1016/j.neuron.2019.11.023 PubMed DOI PMC

Takahashi K., Ohta T. (2017). Membrane translocation of transient receptor potential ankyrin 1 induced by inflammatory cytokines in lung cancer cells. Biochem. Biophys. Res. Commun. 490 587–593. 10.1016/j.bbrc.2017.06.082 PubMed DOI

Talavera K., Startek J. B., Alvarez-Collazo J., Boonen B., Alpizar Y. A., Sanchez A., et al. (2019). Mammalian transient receptor potential TRPA1 channels: from structure to disease. Physiol. Rev. [Epub ahead of print]. PubMed

Ufret-Vincenty C. A., Klein R. M., Hua L., Angueyra J., Gordon S. E. (2011). Localization of the PIP2 sensor of TRPV1 ion channels. J. Biol. Chem. 286 9688–9698. 10.1074/jbc.M110.192526 PubMed DOI PMC

Vandewauw I., De Clercq K., Mulier M., Held K., Pinto S., Van Ranst N., et al. (2018). A TRP channel trio mediates acute noxious heat sensing. Nature 555 662–666. 10.1038/nature26137 PubMed DOI

Viana F. (2016). TRPA1 channels: molecular sentinels of cellular stress and tissue damage. J. Physiol. 594 4151–4169. 10.1113/JP270935 PubMed DOI PMC

Villalobo A., Ishida H., Vogel H. J., Berchtold M. W. (2018). Calmodulin as a protein linker and a regulator of adaptor/scaffold proteins. Biochim. Biophys. Acta Mol. Cell Res. 1865 507–521. 10.1016/j.bbamcr.2017.12.004 PubMed DOI

Viswanath V., Story G. M., Peier A. M., Petrus M. J., Lee V. M., Hwang S. W., et al. (2003). Opposite thermosensor in fruitfly and mouse. Nature 423 822–823. 10.1038/423822a PubMed DOI

Voolstra O., Huber A. (2014). Post-translational modifications of TRP channels. Cells 3 258–287. 10.3390/cells3020258 PubMed DOI PMC

Wang S., Dai Y., Fukuoka T., Yamanaka H., Kobayashi K., Obata K., et al. (2008). Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain. Brain 131(Pt 5), 1241–1251. 10.1093/brain/awn060 PubMed DOI

Wang Y. Y., Chang R. B., Allgood S. D., Silver W. L., Liman E. R. (2011). A TRPA1-dependent mechanism for the pungent sensation of weak acids. J. Gen. Physiol. 137 493–505. 10.1085/jgp.201110615 PubMed DOI PMC

Wang Z., Ye D., Ye J., Wang M., Liu J., Jiang H., et al. (2019). The TRPA1 channel in the cardiovascular system: promising features and challenges. Front. Pharmacol. 10:1253. 10.3389/fphar.2019.01253 PubMed DOI PMC

Weng H. J., Patel K. N., Jeske N. A., Bierbower S. M., Zou W., Tiwari V., et al. (2015). Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron 85 833–846. 10.1016/j.neuron.2014.12.065 PubMed DOI PMC

Witschas K., Jobin M. L., Korkut D. N., Vladan M. M., Salgado G., Lecomte S., et al. (2015). Interaction of a peptide derived from C-terminus of human TRPA1 channel with model membranes mimicking the inner leaflet of the plasma membrane. Biochim. Biophys. Acta 1848 1147–1156. 10.1016/j.bbamem.2015.02.003 PubMed DOI

Yap K. L., Kim J., Truong K., Sherman M., Yuan T., Ikura M. (2000). Calmodulin target database. J. Struct. Funct. Genomics 1 8–14. PubMed

Yarmolinsky D. A., Peng Y., Pogorzala L. A., Rutlin M., Hoon M. A., Zuker C. S. (2016). Coding and Plasticity in the Mammalian Thermosensory System. Neuron 92 1079–1092. 10.1016/j.neuron.2016.10.021 PubMed DOI PMC

Zhang X., Li L., McNaughton P. A. (2008). Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150. Neuron 59 450–461. 10.1016/j.neuron.2008.05.015 PubMed DOI

Zhao J., King Lin J. V., Paulsen C. E., Cheng Y., Julius D. (2019). Mechanisms governing irritant-evoked activation and calcium modulation of TRPA1. BioRxiv [preprint]. 10.1101/2019.12.26.888982 PubMed DOI PMC

Zimova L., Sinica V., Kadkova A., Vyklicka L., Zima V., Barvik I., et al. (2018). Intracellular cavity of sensor domain controls allosteric gating of TRPA1 channel. Sc.Signal. 11:eaan8621. 10.1126/scisignal.aan8621 PubMed DOI

Zurborg S., Yurgionas B., Jira J. A., Caspani O., Heppenstall P. A. (2007). Direct activation of the ion channel TRPA1 by Ca2+. Nat. Neurosci. 10 277–279. 10.1038/nn1843 PubMed DOI

Zygmunt P. M., Hogestatt E. D. (2014). Trpa1. Handb. Exp. Pharmacol. 222 583–630. 10.1007/978-3-642-54215-2_23 PubMed DOI

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