Capsaicin, the main pungent ingredient in ‘hot’ chili peppers, elicits burning pain by activating specific(vanilloid)receptors on sensory nerve endings.The cloned capsaicin receptor(VR1)is a nonselective cation channel with six transmembrane domains that is structurally related to a member of the TRP(transient receptor potential)channel family.VR1 is activated not only by capsaicin but also by increases in temperature that reach the noxious range(>43°C).Protons potentiate the effects of capsaicin or heat on VR1 activity by markedly decreasing the capsaicin concentration or temperature at which the channel is activated.Furthermore, a significant increase in proton concentration(pH<5.9)can evoke channel activity at room temperature.The analysis of single−channel currents in excised membrane patches suggests that capsaicin, heat or protons gate VR1 directly.VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain.VRL−1, a VR1 homologue, is not activated by vanilloids or protons, but can be activated by elevation in ambient temperature exceeding 52°C.These findings indicate that related ion channels may account for thermal responsiveness over a range of noxious temperature.