Extracellular quaternary ammonium blockade of transient receptor potential vanilloid subtype 1 channels expressed in Xenopus laevis oocytes

Ricardo E Rivera-Acevedo; Stephan Alexander Pless; Stephan K W Schwarz; Christopher A Ahern

doi:10.1124/mol.112.079277

Extracellular quaternary ammonium blockade of transient receptor potential vanilloid subtype 1 channels expressed in Xenopus laevis oocytes

Ricardo E Rivera-Acevedo, Stephan Alexander Pless, Stephan K W Schwarz, Christopher A Ahern

3 Citationer (Scopus)

Abstract

Transient receptor potential vanilloid subtype 1 (TRPV1) channels are essential nociceptive integrators in primary afferent neurons. These nonselective cation channels are inhibited by local anesthetic compounds through an undefined mechanism. Here, we show that lidocaine inhibits TRPV1 channels expressed in Xenopus laevis oocytes, whereas the neutral local anesthetic, benzocaine, does not, suggesting that a titratable amine is required for high-affinity inhibition. Consistent with this possibility, extracellular tetraethylammonium (TEA) and tetramethylammonium application produces potent, voltage-dependent pore block. Alanine substitutions at Phe649 and Glu648, residues in the putative TRPV1 pore region, significantly abrogated the concentration-dependent TEA inhibition. The results suggest that large cations, shown previously to enter cells through activated transient receptor potential channels, can also act as channel blockers.

Originalsprog	Engelsk
Tidsskrift	Molecular Pharmacology
Vol/bind	82
Udgave nummer	6
Sider (fra-til)	1129-35
Antal sider	7
ISSN	0026-895X
DOI	https://doi.org/10.1124/mol.112.079277
Status	Udgivet - dec. 2012

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10.1124/mol.112.079277

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Extracellular quaternary ammonium blockade of transient receptor potential vanilloid subtype 1 channels expressed in Xenopus laevis oocytes. / Rivera-Acevedo, Ricardo E; Pless, Stephan Alexander; Schwarz, Stephan K W et al.

I: Molecular Pharmacology, Bind 82, Nr. 6, 12.2012, s. 1129-35.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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title = "Extracellular quaternary ammonium blockade of transient receptor potential vanilloid subtype 1 channels expressed in Xenopus laevis oocytes",

abstract = "Transient receptor potential vanilloid subtype 1 (TRPV1) channels are essential nociceptive integrators in primary afferent neurons. These nonselective cation channels are inhibited by local anesthetic compounds through an undefined mechanism. Here, we show that lidocaine inhibits TRPV1 channels expressed in Xenopus laevis oocytes, whereas the neutral local anesthetic, benzocaine, does not, suggesting that a titratable amine is required for high-affinity inhibition. Consistent with this possibility, extracellular tetraethylammonium (TEA) and tetramethylammonium application produces potent, voltage-dependent pore block. Alanine substitutions at Phe649 and Glu648, residues in the putative TRPV1 pore region, significantly abrogated the concentration-dependent TEA inhibition. The results suggest that large cations, shown previously to enter cells through activated transient receptor potential channels, can also act as channel blockers.",

keywords = "Anesthetics, Local, Animals, Benzocaine, Capsaicin, Lidocaine, Mutation, Oocytes, Quaternary Ammonium Compounds, TRPV Cation Channels, Tetraethylammonium, Xenopus Proteins, Xenopus laevis",

author = "Rivera-Acevedo, {Ricardo E} and Pless, {Stephan Alexander} and Schwarz, {Stephan K W} and Ahern, {Christopher A}",

year = "2012",

month = dec,

doi = "10.1124/mol.112.079277",

language = "English",

volume = "82",

pages = "1129--35",

journal = "Molecular Pharmacology",

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TY - JOUR

T1 - Extracellular quaternary ammonium blockade of transient receptor potential vanilloid subtype 1 channels expressed in Xenopus laevis oocytes

AU - Rivera-Acevedo, Ricardo E

AU - Pless, Stephan Alexander

AU - Schwarz, Stephan K W

AU - Ahern, Christopher A

PY - 2012/12

Y1 - 2012/12

N2 - Transient receptor potential vanilloid subtype 1 (TRPV1) channels are essential nociceptive integrators in primary afferent neurons. These nonselective cation channels are inhibited by local anesthetic compounds through an undefined mechanism. Here, we show that lidocaine inhibits TRPV1 channels expressed in Xenopus laevis oocytes, whereas the neutral local anesthetic, benzocaine, does not, suggesting that a titratable amine is required for high-affinity inhibition. Consistent with this possibility, extracellular tetraethylammonium (TEA) and tetramethylammonium application produces potent, voltage-dependent pore block. Alanine substitutions at Phe649 and Glu648, residues in the putative TRPV1 pore region, significantly abrogated the concentration-dependent TEA inhibition. The results suggest that large cations, shown previously to enter cells through activated transient receptor potential channels, can also act as channel blockers.

AB - Transient receptor potential vanilloid subtype 1 (TRPV1) channels are essential nociceptive integrators in primary afferent neurons. These nonselective cation channels are inhibited by local anesthetic compounds through an undefined mechanism. Here, we show that lidocaine inhibits TRPV1 channels expressed in Xenopus laevis oocytes, whereas the neutral local anesthetic, benzocaine, does not, suggesting that a titratable amine is required for high-affinity inhibition. Consistent with this possibility, extracellular tetraethylammonium (TEA) and tetramethylammonium application produces potent, voltage-dependent pore block. Alanine substitutions at Phe649 and Glu648, residues in the putative TRPV1 pore region, significantly abrogated the concentration-dependent TEA inhibition. The results suggest that large cations, shown previously to enter cells through activated transient receptor potential channels, can also act as channel blockers.

KW - Anesthetics, Local

KW - Animals

KW - Benzocaine

KW - Capsaicin

KW - Lidocaine

KW - Mutation

KW - Oocytes

KW - Quaternary Ammonium Compounds

KW - TRPV Cation Channels

KW - Tetraethylammonium

KW - Xenopus Proteins

KW - Xenopus laevis

U2 - 10.1124/mol.112.079277

DO - 10.1124/mol.112.079277

M3 - Journal article

C2 - 22956771

SN - 0026-895X

VL - 82

SP - 1129

EP - 1135

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 6

ER -

Extracellular quaternary ammonium blockade of transient receptor potential vanilloid subtype 1 channels expressed in Xenopus laevis oocytes

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