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Biophys J
2013 Feb 19;1044:798-806. doi: 10.1016/j.bpj.2013.01.008.
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Characterization of a ligand binding site in the human transient receptor potential ankyrin 1 pore.
Klement G
,
Eisele L
,
Malinowsky D
,
Nolting A
,
Svensson M
,
Terp G
,
Weigelt D
,
Dabrowski M
.
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The pharmacology and regulation of Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel activity is intricate due to the physiological function as an integrator of multiple chemical, mechanical, and temperature stimuli as well as differences in species pharmacology. In this study, we describe and compare the current inhibition efficacy of human TRPA1 on three different TRPA1 antagonists. We used a homology model of TRPA1 based on Kv1.2 to select pore vestibule residues available for interaction with ligands entering the vestibule. Site-directed mutation constructs were expressed in Xenopus oocytes and their functionality and pharmacology assessed to support and improve our homology model. Based on the functional pharmacology results we propose an antagonist-binding site in the vestibule of the TRPA1 ion channel. We use the results to describe the proposed intravestibular ligand-binding site in TRPA1 in detail. Based on the single site substitutions, we designed a human TRPA1 receptor by substituting several residues in the vestibule and adjacent regions from the rat receptor to address and explain observed species pharmacology differences. In parallel, the lack of effect on HC-030031 inhibition by the vestibule substitutions suggests that this molecule interacts with TRPA1 via a binding site not situated in the vestibule.
Bandell,
Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.
2004, Pubmed
Bandell,
Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.
2004,
Pubmed
Banke,
Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation.
2010,
Pubmed
Bautista,
TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.
2006,
Pubmed
Benedikt,
Essential role for the putative S6 inner pore region in the activation gating of the human TRPA1 channel.
2009,
Pubmed
Bianchi,
Species comparison and pharmacological characterization of human, monkey, rat, and mouse TRPA1 channels.
2012,
Pubmed
Chen,
Pore dilation occurs in TRPA1 but not in TRPM8 channels.
2009,
Pubmed
Chen,
Molecular determinants of species-specific activation or blockade of TRPA1 channels.
2008,
Pubmed
Chen,
Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.
2011,
Pubmed
Corey,
TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells.
2004,
Pubmed
Eid,
HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity.
2008,
Pubmed
Fajardo,
TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence.
2008,
Pubmed
Gaudet,
TRP channels entering the structural era.
2008,
Pubmed
Hinman,
TRP channel activation by reversible covalent modification.
2006,
Pubmed
Hoenderop,
Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6.
2003,
Pubmed
,
Xenbase
Hu,
Zinc activates damage-sensing TRPA1 ion channels.
2009,
Pubmed
Jordt,
Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.
2004,
Pubmed
Karashima,
TRPA1 acts as a cold sensor in vitro and in vivo.
2009,
Pubmed
Klionsky,
Species-specific pharmacology of Trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists.
2007,
Pubmed
Kremeyer,
A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.
2010,
Pubmed
Kwan,
TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction.
2006,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Macpherson,
The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin.
2005,
Pubmed
Macpherson,
Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines.
2007,
Pubmed
McNamara,
TRPA1 mediates formalin-induced pain.
2007,
Pubmed
Nilius,
The transient receptor potential family of ion channels.
2011,
Pubmed
Ramsey,
An introduction to TRP channels.
2006,
Pubmed
Story,
ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.
2003,
Pubmed
Trevisani,
4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.
2007,
Pubmed
Vallin,
N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor.
2012,
Pubmed
Vannier,
The membrane topology of human transient receptor potential 3 as inferred from glycosylation-scanning mutagenesis and epitope immunocytochemistry.
1998,
Pubmed
Wang,
The nociceptor ion channel TRPA1 is potentiated and inactivated by permeating calcium ions.
2008,
Pubmed
Xiao,
Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels.
2008,
Pubmed
Zurborg,
Direct activation of the ion channel TRPA1 by Ca2+.
2007,
Pubmed
