TRPV1 is activated by both acidic and basic pH.
Maintaining physiological pH is required for survival, and exposure to alkaline chemicals such as ammonia (smelling salts) elicits severe pain and inflammation through unknown mechanisms. TRPV1, the capsaicin receptor, is an integrator of noxious stimuli including heat and extracellular acidic pH. Here, we report that ammonia activates TRPV1, TRPA1 (another polymodal nocisensor), and other unknown receptor(s) expressed in sensory neurons. Ammonia and intracellular alkalization activate TRPV1 through a mechanism that involves a cytoplasmic histidine residue, not used by other TRPV1 agonists such as heat, capsaicin or low pH. Our studies show that TRPV1 detects both acidic and basic deviations from homeostatic pH.
Dhaka
Ajay
A
Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Uzzell
Valerie
V
Dubin
Adrienne E
AE
Mathur
Jayanti
J
Petrus
Matt
M
Bandell
Michael
M
Patapoutian
Ardem
A
D000143:Acids / Q000494:pharmacology*; D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002461:Cell Line, Transformed; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008164:Luminescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed / Q000379:methods; D018408:Patch-Clamp Techniques; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000187:drug effects*; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D000143:Acids; D008164:Luminescent Proteins; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011719:Pyrazines; D011725:Pyridines; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000643:Ammonium Chloride; D002211:Capsaicin; D002118:Calcium