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Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines

The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperat... Full description

Journal Title: Nature 2007, Vol.445 (7127), p.541-545
Main Author: MACPHERSON, Lindsey J
Other Authors: DUBIN, Adrienne E , EVANS, Michael J , MARR, Felix , SCHULTZ, Peter G , CRAVATT, Benjamin F , PATAPOUTIAN, Ardem
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: Nature Publishing
ID: ISSN: 0028-0836
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title: Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines
format: Article
creator:
  • MACPHERSON, Lindsey J
  • DUBIN, Adrienne E
  • EVANS, Michael J
  • MARR, Felix
  • SCHULTZ, Peter G
  • CRAVATT, Benjamin F
  • PATAPOUTIAN, Ardem
subjects:
  • Acrolein - analogs & derivatives
  • Acrolein - chemistry
  • Acrolein - metabolism
  • Acrolein - pharmacology
  • Animals
  • Biological and medical sciences
  • Cysteine - chemistry
  • Cysteine - metabolism
  • Disulfides - chemistry
  • Disulfides - metabolism
  • Dithiothreitol - pharmacology
  • Electric Conductivity
  • Ethyl Methanesulfonate - analogs & derivatives
  • Ethyl Methanesulfonate - chemistry
  • Ethyl Methanesulfonate - metabolism
  • Ethyl Methanesulfonate - pharmacology
  • Fundamental and applied biological sciences. Psychology
  • Humans
  • Ion Channel Gating - drug effects
  • Mice
  • Mustard Plant - chemistry
  • Mustard Plant - metabolism
  • Noxae - chemistry
  • Noxae - metabolism
  • Noxae - pharmacology
  • Pain - chemically induced
  • Pain - physiopathology
  • Plant Oils - chemistry
  • Plant Oils - metabolism
  • Plant Oils - pharmacology
  • Somesthesis and somesthetic pathways (proprioception, exteroception, nociception)
  • interoception
  • electrolocation. Sensory receptors
  • Transient Receptor Potential Channels - agonists
  • Transient Receptor Potential Channels - chemistry
  • Transient Receptor Potential Channels - metabolism
  • Vertebrates: nervous system and sense organs
ispartof: Nature, 2007, Vol.445 (7127), p.541-545
description: The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
  • 1476-4679
url: Link


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titleNoxious compounds activate TRPA1 ion channels through covalent modification of cysteines
creatorMACPHERSON, Lindsey J ; DUBIN, Adrienne E ; EVANS, Michael J ; MARR, Felix ; SCHULTZ, Peter G ; CRAVATT, Benjamin F ; PATAPOUTIAN, Ardem
creatorcontribMACPHERSON, Lindsey J ; DUBIN, Adrienne E ; EVANS, Michael J ; MARR, Felix ; SCHULTZ, Peter G ; CRAVATT, Benjamin F ; PATAPOUTIAN, Ardem
descriptionThe nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.
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languageeng
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subjectAcrolein - analogs & derivatives ; Acrolein - chemistry ; Acrolein - metabolism ; Acrolein - pharmacology ; Animals ; Biological and medical sciences ; Cysteine - chemistry ; Cysteine - metabolism ; Disulfides - chemistry ; Disulfides - metabolism ; Dithiothreitol - pharmacology ; Electric Conductivity ; Ethyl Methanesulfonate - analogs & derivatives ; Ethyl Methanesulfonate - chemistry ; Ethyl Methanesulfonate - metabolism ; Ethyl Methanesulfonate - pharmacology ; Fundamental and applied biological sciences. Psychology ; Humans ; Ion Channel Gating - drug effects ; Mice ; Mustard Plant - chemistry ; Mustard Plant - metabolism ; Noxae - chemistry ; Noxae - metabolism ; Noxae - pharmacology ; Pain - chemically induced ; Pain - physiopathology ; Plant Oils - chemistry ; Plant Oils - metabolism ; Plant Oils - pharmacology ; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors ; Transient Receptor Potential Channels - agonists ; Transient Receptor Potential Channels - chemistry ; Transient Receptor Potential Channels - metabolism ; Vertebrates: nervous system and sense organs
ispartofNature, 2007, Vol.445 (7127), p.541-545
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1DUBIN, Adrienne E
2EVANS, Michael J
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4SCHULTZ, Peter G
5CRAVATT, Benjamin F
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descriptionThe nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.
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0Acrolein - analogs & derivatives
1Acrolein - chemistry
2Acrolein - metabolism
3Acrolein - pharmacology
4Animals
5Biological and medical sciences
6Cysteine - chemistry
7Cysteine - metabolism
8Disulfides - chemistry
9Disulfides - metabolism
10Dithiothreitol - pharmacology
11Electric Conductivity
12Ethyl Methanesulfonate - analogs & derivatives
13Ethyl Methanesulfonate - chemistry
14Ethyl Methanesulfonate - metabolism
15Ethyl Methanesulfonate - pharmacology
16Fundamental and applied biological sciences. Psychology
17Humans
18Ion Channel Gating - drug effects
19Mice
20Mustard Plant - chemistry
21Mustard Plant - metabolism
22Noxae - chemistry
23Noxae - metabolism
24Noxae - pharmacology
25Pain - chemically induced
26Pain - physiopathology
27Plant Oils - chemistry
28Plant Oils - metabolism
29Plant Oils - pharmacology
30Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors
31Transient Receptor Potential Channels - agonists
32Transient Receptor Potential Channels - chemistry
33Transient Receptor Potential Channels - metabolism
34Vertebrates: nervous system and sense organs
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titleNoxious compounds activate TRPA1 ion channels through covalent modification of cysteines
authorMACPHERSON, Lindsey J ; DUBIN, Adrienne E ; EVANS, Michael J ; MARR, Felix ; SCHULTZ, Peter G ; CRAVATT, Benjamin F ; PATAPOUTIAN, Ardem
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1Acrolein - chemistry
2Acrolein - metabolism
3Acrolein - pharmacology
4Animals
5Biological and medical sciences
6Cysteine - chemistry
7Cysteine - metabolism
8Disulfides - chemistry
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18Ion Channel Gating - drug effects
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20Mustard Plant - chemistry
21Mustard Plant - metabolism
22Noxae - chemistry
23Noxae - metabolism
24Noxae - pharmacology
25Pain - chemically induced
26Pain - physiopathology
27Plant Oils - chemistry
28Plant Oils - metabolism
29Plant Oils - pharmacology
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31Transient Receptor Potential Channels - agonists
32Transient Receptor Potential Channels - chemistry
33Transient Receptor Potential Channels - metabolism
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abstractThe nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.
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