TRPV1 acts as proton channel to induce acidification in nociceptive neurons.
The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca(2+)-dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na(+), Mg(2+), and Ca(2+). The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons.
Hellwig
Nicole
N
Department of Pharmacology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany.
Plant
Tim D
TD
Janson
Wiebke
W
Schäfer
Michael
M
Schultz
Günter
G
Schaefer
Michael
M
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004594:Electrophysiology; D031541:Fluorescence Resonance Energy Transfer; D005727:Ganglia, Spinal / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008164:Luminescent Proteins / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry; D008297:Male; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000378:metabolism / Q000502:physiology*; D012964:Sodium / Q000737:chemistry; D013050:Spectrometry, Fluorescence
D001426:Bacterial Proteins; D008164:Luminescent Proteins; D011522:Protons; D011955:Receptors, Drug; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D012964:Sodium; D008274:Magnesium; D002118:Calcium