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) re ceptor). ATP induces a cationic current in HEK293 cells transfected wi th the P2X(4) receptor. However, the current is almost completely inse nsitive to antagonists effective at other P-2X receptors. Sensitivity to two of these antagonists (pyridosalphosphate-6-azophenyl-2',4'-disu lfonic acid and pyridoxal 5-phosphate) is restored by replacement of G lu249 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 sa livary glands, Recordings from rat submandibular gland cells showed AT P-induced currents that are also insensitive to antagonists, These res ults define a further member of P-2X receptor family, and they identif y an amino acid residue involved in antagonist binding, They also intr oduce a new phenotype for ATP responses at P-2X receptors-insensitivit y to currently known antagonists.