TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

• Published in: The Journal of biological chemistry Vol. 279; no. 33; pp. 34553 - 34561
• Main Authors: Hellwig, Nicole, Plant, Tim D, Janson, Wiebke, Schäfer, Michael, Schultz, Günter, Schaefer, Michael
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 13-08-2004
• Subjects: Animals; Bacterial Proteins - metabolism; Calcium - chemistry; Calcium - metabolism; Cell Line; Electrophysiology; Fluorescence Resonance Energy Transfer; Ganglia, Spinal - metabolism; Green Fluorescent Proteins; Humans; Hydrogen-Ion Concentration; Luminescent Proteins - metabolism; Magnesium - chemistry; Male; Microscopy, Confocal; Neurons - metabolism; Nociceptors - metabolism; Protons; Rats; Rats, Wistar; Receptors, Drug - metabolism; Receptors, Drug - physiology; Sodium - chemistry; Spectrometry, Fluorescence
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M402966200

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.