An antagonist-insensitive P-2X receptor expressed in epithelia and brain

A cDNA was cloned which encodes a new ATP-gated ion channel (P2X(4) receptor). ATP induces a cationic current in HEK293 cells transfected with the P2X(4) receptor. However, the current is almost completely insensitive to antagonists effective at other P-2X receptors. Sensitivity to two of these antagonists (pyridosalphosphate-6-azophenyl-2',4'-disulfonic acid and pyridoxal 5-phosphate) is restored by replacement of Glu249 by lysine, which occurs at the equivalent position in P2X(1) and P2X(2) receptors. P2X(4) RNA is found by in situ hybridization in the brain, peripheral ganglia and epithelia including serosal cells of salivary glands, Recordings from rat submandibular gland cells showed ATP-induced currents that are also insensitive to antagonists, These results define a further member of P-2X receptor family, and they identify an amino acid residue involved in antagonist binding, They also introduce a new phenotype for ATP responses at P-2X receptors-insensitivity to currently known antagonists.