Dr Laura Sadofsky L.R.Sadofsky@hull.ac.uk
Senior Lecturer in Respiratory Medicine
TRPA1 is activated by direct addition of cysteine residues to the N-hydroxysuccinyl esters of acrylic and cinnamic acids
Sadofsky, Laura; Sadofsky, Laura R.; Morice, Alyn; Boa, Andrew N.; Boa, Andrew; Maher, Sarah A.; Birrell, Mark A.; Belvisi, Maria G.; Morice, Alyn H.
Authors
Dr Laura Sadofsky L.R.Sadofsky@hull.ac.uk
Senior Lecturer in Respiratory Medicine
Professor Alyn Morice A.H.Morice@hull.ac.uk
Foundation Chair and Professor of Respiratory Medicine
Dr Andrew Boa A.N.Boa@hull.ac.uk
Senior Lecturer
Dr Andrew Boa A.N.Boa@hull.ac.uk
Senior Lecturer
Sarah A. Maher
Mark A. Birrell
Maria G. Belvisi
Professor Alyn Morice A.H.Morice@hull.ac.uk
Foundation Chair and Professor of Respiratory Medicine
Abstract
The nociceptor TRPA1 is thought to be activated through covalent modification of specific cysteine residues on the N terminal of the channel. The precise mechanism of covalent modification with unsaturated carbonyl-containing compounds is unclear, therefore by examining a range of compounds which can undergo both conjugate and/or direct addition reactions we sought to further elucidate the mechanism(s) whereby TRPA1 can be activated by covalent modification. Calcium signalling was used to determine the mechanism of activation of TRPA1 expressed in HEK293 cells with a series of related compounds which were capable of either direct and/or conjugate addition processes. These results were confirmed using physiological recordings with isolated vagus nerve preparations. We found negligible channel activation with chemicals which could only react with cysteine residues via conjugate addition such as acrylamide, acrylic acid, and cinnamic acid. Compounds able to react via either conjugate or direct addition, such as acrolein, methyl vinyl ketone, mesityl oxide, acrylic acid NHS ester, cinnamaldehyde and cinnamic acid NHS ester, activated TRPA1 in a concentration dependent manner as did compounds only capable of direct addition, namely propionic acid NHS ester and hydrocinnamic acid NHS ester. These compounds failed to activate TRPV1 expressed in HEK293 cells or mock transfected HEK293 cells. For molecules capable of direct or conjugate additions, the results suggest for the first time that TRPA1 may be activated preferentially by direct addition of the thiol group of TRPA1 cysteines to the agonist carbonyl carbon of α,β-unsaturated carbonyl-containing compounds.
Citation
Sadofsky, L. R., Boa, A. N., Maher, S. A., Birrell, M. A., Belvisi, M. G., & Morice, A. H. (2011). TRPA1 is activated by direct addition of cysteine residues to the N-hydroxysuccinyl esters of acrylic and cinnamic acids. Pharmacological research : the official journal of the Italian Pharmacological Society, 63(1), 30-36. https://doi.org/10.1016/j.phrs.2010.11.004
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 11, 2010 |
Online Publication Date | Nov 19, 2010 |
Publication Date | 2011-01 |
Journal | Pharmacological Research |
Print ISSN | 1043-6618 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 63 |
Issue | 1 |
Pages | 30-36 |
DOI | https://doi.org/10.1016/j.phrs.2010.11.004 |
Keywords | Transient receptor potential ankyrin 1; TRPA1; Cysteine covalent modification; Direct addition; N-Hydroxysuccinyl esters |
Public URL | https://hull-repository.worktribe.com/output/424074 |
Publisher URL | https://www.sciencedirect.com/science/article/abs/pii/S1043661810002173?via%3Dihub |
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