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Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1.
J Biol Chem. 2008 Apr 04; 283(14):9377-87.JB

Abstract

Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors and activated by capsaicin. TRPV1 detects diverse stimuli, including acid, heat, and endogenous vanilloids, and functions as a molecular integrator of pain perception. Herein we demonstrate a novel regulatory role of extracellular Na(+) ([Na(+)](o)) on TRPV1 function. In human embryonic kidney 293 cells expressing porcine TRPV1, low [Na(+)](o) evoked increases of [Ca(2+)](i) that were suppressed by TRPV1 antagonists and facilitated responses to capsaicin, protons, heat, and an endovanilloid. [Na(+)](o) removal simultaneously elicited a [Ca(2+)](i) increase and outward-rectified current with a reversal potential similar to those of capsaicin. Neutralization of the two acidic residues which confer the proton sensitivity to TRPV1 resulted in a reduction of low [Na(+)](o)-induced responses. In primary culture of porcine sensory neurons, the removal of [Na(+)](o) produced a [Ca(2+)](i) increase and current responses only in the cells responding to capsaicin. Low [Na(+)](o) evoked a [Ca(2+)](i) increase in sensory neurons of wild type mice, but not TRPV1-null mice, and in human embryonic kidney 293 cells expressing human TRPV1. The present results suggest that [Na(+)](o) negatively regulates the gating and polymodal sensitization of the TRPV1 channel. [Na(+)](o) surrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions.

Authors+Show Affiliations

Laboratory of Pharmacology, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. tohta@vetmed.hokudai.ac.jpNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18230619

Citation

Ohta, Toshio, et al. "Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1): Tonic Inhibitory Regulation of Extracellular Sodium Through the External Protonation Sites On TRPV1." The Journal of Biological Chemistry, vol. 283, no. 14, 2008, pp. 9377-87.
Ohta T, Imagawa T, Ito S. Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1. J Biol Chem. 2008;283(14):9377-87.
Ohta, T., Imagawa, T., & Ito, S. (2008). Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1. The Journal of Biological Chemistry, 283(14), 9377-87. https://doi.org/10.1074/jbc.M709377200
Ohta T, Imagawa T, Ito S. Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1): Tonic Inhibitory Regulation of Extracellular Sodium Through the External Protonation Sites On TRPV1. J Biol Chem. 2008 Apr 4;283(14):9377-87. PubMed PMID: 18230619.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1. AU - Ohta,Toshio, AU - Imagawa,Toshiaki, AU - Ito,Shigeo, Y1 - 2008/01/29/ PY - 2008/1/31/pubmed PY - 2008/5/23/medline PY - 2008/1/31/entrez SP - 9377 EP - 87 JF - The Journal of biological chemistry JO - J Biol Chem VL - 283 IS - 14 N2 - Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors and activated by capsaicin. TRPV1 detects diverse stimuli, including acid, heat, and endogenous vanilloids, and functions as a molecular integrator of pain perception. Herein we demonstrate a novel regulatory role of extracellular Na(+) ([Na(+)](o)) on TRPV1 function. In human embryonic kidney 293 cells expressing porcine TRPV1, low [Na(+)](o) evoked increases of [Ca(2+)](i) that were suppressed by TRPV1 antagonists and facilitated responses to capsaicin, protons, heat, and an endovanilloid. [Na(+)](o) removal simultaneously elicited a [Ca(2+)](i) increase and outward-rectified current with a reversal potential similar to those of capsaicin. Neutralization of the two acidic residues which confer the proton sensitivity to TRPV1 resulted in a reduction of low [Na(+)](o)-induced responses. In primary culture of porcine sensory neurons, the removal of [Na(+)](o) produced a [Ca(2+)](i) increase and current responses only in the cells responding to capsaicin. Low [Na(+)](o) evoked a [Ca(2+)](i) increase in sensory neurons of wild type mice, but not TRPV1-null mice, and in human embryonic kidney 293 cells expressing human TRPV1. The present results suggest that [Na(+)](o) negatively regulates the gating and polymodal sensitization of the TRPV1 channel. [Na(+)](o) surrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18230619/Novel_gating_and_sensitizing_mechanism_of_capsaicin_receptor__TRPV1_:_tonic_inhibitory_regulation_of_extracellular_sodium_through_the_external_protonation_sites_on_TRPV1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)52904-9 DB - PRIME DP - Unbound Medicine ER -