A role for calcineurin in the desensitization of the P2X₃ receptor

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.