Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling.

Abstract

Transient receptor potential (TRP) channels detect diverse sensory stimuli, including alterations in osmolarity. However, a molecular detector of noxious hypertonic stimuli has not yet been identified. We show here that acute pain-related behavior evoked by elevated ionic strength is abolished in TRP vanilloid subtype 1 (TRPV1)-null mice and inhibited by iodoresiniferatoxin, a potent TRPV1 antagonist. Electrophysiological recordings demonstrate a novel form of ion channel modulation by which extracellular Na+, Mg2+, and Ca2+ ions sensitize and activate the capsaicin receptor, TRPV1. At room temperature, increasing extracellular Mg2+ (from 1 to 5 mM) or Na+ (+50 mM) increased ligand-activated currents up to fourfold, and 10 mM Mg2+ reduced the EC50 for activation by capsaicin from 890 to 450 nM. Moreover, concentrations of divalent cations >10 mM directly gate the receptor. These effects occur via electrostatic interactions with two glutamates (E600 and E648) formerly identified as proton-binding residues. Furthermore, phospholipase C-mediated signaling enhances the effects of cations, and physiological concentrations of cations contribute to the bradykinin-evoked activation of TRPV1 and the sensitization of the receptor to heat. Thus, the modulation of TRPV1 by cationic strength may contribute to inflammatory pain signaling.

• Authors: Gerard P Ahern, Ian M Brooks, Rosa Linda Miyares, Xiang-bin Wang
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 25 Issue 21 Pg. 5109-16 (May 25 2005) ISSN: 1529-2401 [Electronic] United States
• PMID: 15917451 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aminobutyrates
• Arachidonic Acids
• Calcium Channel Blockers
• Cations
• Endocannabinoids
• N(gamma)-acetyl-2,4-diaminobutyric acid
• Polyunsaturated Alkamides
• TRPV Cation Channels
• TRPV1 protein, mouse
• Phorbol 12,13-Dibutyrate
• Magnesium Sulfate
• Adenosine Triphosphate
• Protein Kinase C
• Capsaicin
• Bradykinin
• Calcium
• anandamide

Topics

• Adenosine Triphosphate (pharmacology)
• Aminobutyrates
• Animals
• Arachidonic Acids (pharmacology)
• Behavior, Animal (physiology)
• Bradykinin
• Calcium (pharmacology)
• Calcium Channel Blockers
• Capsaicin (pharmacology)
• Cations (pharmacology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Drug Interactions
• Electric Stimulation (methods)
• Endocannabinoids
• Extracellular Space (drug effects, metabolism)
• Humans
• Hydrogen-Ion Concentration
• Magnesium Sulfate (pharmacology)
• Membrane Potentials (drug effects, physiology, radiation effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microinjections
• Models, Biological
• Mutagenesis
• Neurons (drug effects, physiology)
• Nodose Ganglion (cytology)
• Oocytes
• Pain (chemically induced, genetics, physiopathology)
• Patch-Clamp Techniques (methods)
• Phorbol 12,13-Dibutyrate (pharmacology)
• Polyunsaturated Alkamides
• Protein Kinase C
• Signal Transduction (drug effects, physiology, radiation effects)
• TRPV Cation Channels (deficiency, physiology)
• Temperature
• Time Factors
• Transfection (methods)