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.
Footnotes
This work was supported in part by the Canada Foundation for Innovation, the British Columbia Knowledge Development Fund (to S.K.W.S. and C.A.A.), the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research (to C.A.A.), the Michael Smith Foundation for Health Research (to C.A.A. and S.A.P.), the Canadian Institutes of Health Research [Banting postdoctoral fellowship] (to S.A.P.), and the St. Pauls Hospital Department of Anesthesia, Vancouver, BC (to R.E.R-.A.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- TRP
- transient receptor potential
- TRPV1
- transient receptor potential vanilloid subtype 1
- Kv
- voltage-gated potassium
- LA
- local anesthetic
- QX-314
- N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium
- TEA
- tetraethylammonium
- TMA
- tetramethylammonium
- QA
- quaternary ammonium.
- Received April 12, 2012.
- Accepted September 4, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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