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.
MeSH terms
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Adenosine Triphosphate / pharmacology
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Aminobutyrates
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Animals
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Arachidonic Acids / pharmacology
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Behavior, Animal / physiology
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Bradykinin
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Calcium / pharmacology
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Calcium Channel Blockers
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Capsaicin / pharmacology
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Cations / pharmacology*
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Cells, Cultured
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Dose-Response Relationship, Drug
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Dose-Response Relationship, Radiation
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Drug Interactions
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Electric Stimulation / methods
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Endocannabinoids
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Extracellular Space / drug effects
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Extracellular Space / metabolism*
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Humans
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Hydrogen-Ion Concentration
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Magnesium Sulfate / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microinjections
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Models, Biological
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Mutagenesis
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Neurons / drug effects
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Neurons / physiology
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Nodose Ganglion / cytology
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Oocytes
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Pain / chemically induced
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Pain / genetics
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Pain / physiopathology*
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Patch-Clamp Techniques / methods
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Phorbol 12,13-Dibutyrate / pharmacology
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Polyunsaturated Alkamides
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Protein Kinase C
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Signal Transduction / radiation effects
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TRPV Cation Channels / deficiency
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TRPV Cation Channels / physiology*
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Temperature
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Time Factors
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Transfection / methods
Substances
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Aminobutyrates
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Arachidonic Acids
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Calcium Channel Blockers
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Cations
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Endocannabinoids
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N(gamma)-acetyl-2,4-diaminobutyric acid
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Polyunsaturated Alkamides
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TRPV Cation Channels
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TRPV1 protein, mouse
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Phorbol 12,13-Dibutyrate
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Magnesium Sulfate
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Adenosine Triphosphate
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Protein Kinase C
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Capsaicin
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Bradykinin
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Calcium
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anandamide