The capsaicin receptor TRPV1 (also known as the vanilloid receptor VR1) is a non-selective cation channel and is activated not only by capsaicin but also by noxious heat or protons. Tissue damage associated with infection, inflammation or ischaemia, produces an array of chemical mediators that activate or sensitize nociceptor terminals. An important component of this pro-algeic response is ATP. In cells expressing TRPV1, ATP increased the currents evoked by capsaicin or protons through activation of P2Y metabotropic receptors in a PKC-dependent manner. In the presence of ATP, the temperature threshold for TRPV1 activation was reduced from 42 degrees C to 35 degrees C, such that normal body temperature could activate TRPV1. Functional interaction between P2Y receptors and TRPV1 was confirmed in a behavioural analysis using TRPV1-deficient mice. Direct phosphorylation of TRPV1 by PKC was confirmed biochemically and the two serine residues involved were identified. Extracellular Ca2+ -dependent desensitization of TRPV1 is thought to be one mechanism underlying the paradoxical effectiveness of capsaicin as an analgesic therapy. The Ca2+ -binding protein calmodulin binds to the C-terminus of TRPV1. We found that disruption of the calmodulin binding segment prevented TRPV1 desensitization even in the presence of extracellular Ca2+.