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The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6.
J Biol Chem. 2013 Jul 12; 288(28):20280-92.JB

Abstract

The surveillance of acid-base homeostasis is concerted by diverse mechanisms, including an activation of sensory afferents. Proton-evoked activation of rodent sensory neurons is mainly mediated by the capsaicin receptor TRPV1 and acid-sensing ion channels. In this study, we demonstrate that extracellular acidosis activates and sensitizes the human irritant receptor TRPA1 (hTRPA1). Proton-evoked membrane currents and calcium influx through hTRPA1 occurred at physiological acidic pH values, were concentration-dependent, and were blocked by the selective TRPA1 antagonist HC030031. Both rodent and rhesus monkey TRPA1 failed to respond to extracellular acidosis, and protons even inhibited rodent TRPA1. Accordingly, mouse dorsal root ganglion neurons lacking TRPV1 only responded to protons when hTRPA1 was expressed heterologously. This species-specific activation of hTRPA1 by protons was reversed in both mouse and rhesus monkey TRPA1 by exchange of distinct residues within transmembrane domains 5 and 6. Furthermore, protons seem to interact with an extracellular interaction site to gate TRPA1 and not via a modification of intracellular N-terminal cysteines known as important interaction sites for electrophilic TRPA1 agonists. Our data suggest that hTRPA1 acts as a sensor for extracellular acidosis in human sensory neurons and should thus be taken into account as a yet unrecognized transduction molecule for proton-evoked pain and inflammation. The species specificity of this property is unique among known endogenous TRPA1 agonists, possibly indicating that evolutionary pressure enforced TRPA1 to inherit the role as an acid sensor in human sensory neurons.

Authors+Show Affiliations

Department of Anesthesia and Critical Care Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. delaroche.jeanne@mh-hannover.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23709225

Citation

de la Roche, Jeanne, et al. "The Molecular Basis for Species-specific Activation of Human TRPA1 Protein By Protons Involves Poorly Conserved Residues Within Transmembrane Domains 5 and 6." The Journal of Biological Chemistry, vol. 288, no. 28, 2013, pp. 20280-92.
de la Roche J, Eberhardt MJ, Klinger AB, et al. The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6. J Biol Chem. 2013;288(28):20280-92.
de la Roche, J., Eberhardt, M. J., Klinger, A. B., Stanslowsky, N., Wegner, F., Koppert, W., Reeh, P. W., Lampert, A., Fischer, M. J., & Leffler, A. (2013). The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6. The Journal of Biological Chemistry, 288(28), 20280-92. https://doi.org/10.1074/jbc.M113.479337
de la Roche J, et al. The Molecular Basis for Species-specific Activation of Human TRPA1 Protein By Protons Involves Poorly Conserved Residues Within Transmembrane Domains 5 and 6. J Biol Chem. 2013 Jul 12;288(28):20280-92. PubMed PMID: 23709225.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6. AU - de la Roche,Jeanne, AU - Eberhardt,Mirjam J, AU - Klinger,Alexandra B, AU - Stanslowsky,Nancy, AU - Wegner,Florian, AU - Koppert,Wolfgang, AU - Reeh,Peter W, AU - Lampert,Angelika, AU - Fischer,Michael J M, AU - Leffler,Andreas, Y1 - 2013/05/24/ PY - 2013/5/28/entrez PY - 2013/5/28/pubmed PY - 2013/9/28/medline KW - Acid-sensing Ion Channels (ASIC) KW - Acidosis KW - Nociceptor KW - Pain KW - Patch Clamp KW - Species Specificity KW - TRP Channels SP - 20280 EP - 92 JF - The Journal of biological chemistry JO - J Biol Chem VL - 288 IS - 28 N2 - The surveillance of acid-base homeostasis is concerted by diverse mechanisms, including an activation of sensory afferents. Proton-evoked activation of rodent sensory neurons is mainly mediated by the capsaicin receptor TRPV1 and acid-sensing ion channels. In this study, we demonstrate that extracellular acidosis activates and sensitizes the human irritant receptor TRPA1 (hTRPA1). Proton-evoked membrane currents and calcium influx through hTRPA1 occurred at physiological acidic pH values, were concentration-dependent, and were blocked by the selective TRPA1 antagonist HC030031. Both rodent and rhesus monkey TRPA1 failed to respond to extracellular acidosis, and protons even inhibited rodent TRPA1. Accordingly, mouse dorsal root ganglion neurons lacking TRPV1 only responded to protons when hTRPA1 was expressed heterologously. This species-specific activation of hTRPA1 by protons was reversed in both mouse and rhesus monkey TRPA1 by exchange of distinct residues within transmembrane domains 5 and 6. Furthermore, protons seem to interact with an extracellular interaction site to gate TRPA1 and not via a modification of intracellular N-terminal cysteines known as important interaction sites for electrophilic TRPA1 agonists. Our data suggest that hTRPA1 acts as a sensor for extracellular acidosis in human sensory neurons and should thus be taken into account as a yet unrecognized transduction molecule for proton-evoked pain and inflammation. The species specificity of this property is unique among known endogenous TRPA1 agonists, possibly indicating that evolutionary pressure enforced TRPA1 to inherit the role as an acid sensor in human sensory neurons. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23709225/The_molecular_basis_for_species_specific_activation_of_human_TRPA1_protein_by_protons_involves_poorly_conserved_residues_within_transmembrane_domains_5_and_6_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)45599-1 DB - PRIME DP - Unbound Medicine ER -