The sensory neurone-specific ATP-gated cation channel P2X3, when expressed in Xenopus oocytes, desensitizes rapidly. Complete removal of extracellular calcium abolishes desensitization. Pretreatment of oocytes with cyclosporin also abolishes P2X3 desensitization. When the calcineurin auto-inhibitory peptide (CaN A457-481) was injected into oocytes, the rate of desensitization of P2X3 decreased on consecutive applications of ATP, suggesting a role for calcineurin in the regulation of desensitization. Truncated P2X3 clones initiating at Met-75 lack the N-terminal intracellular region, but express functional channels in oocytes that do not desensitize. Taken together, these data suggest that P2X3 desensitizes through a calcium-dependent calcineurin-mediated dephosphorylation involving N-terminal residues that are phosphorylated in functional channels.