Acid potentiation of the capsaicin receptor determined by a key extracellular site

Abstract

The capsaicin receptor, VR1, is a sensory neuron‐specific ion channel that serves as a detector of pain‐producing chemical and physical stimuli. The response of VR1 to capsaicin or heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, ischemia or tumor growth. A molecular determinant for this activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the pore region of the channel. This residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in proton concentration. We also show that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton‐evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus‐specific steps in VR1 activation and offer strategies for the development of analgesic agents.