A NOVEL NEURONAL P-2X ATP RECEPTOR-ION CHANNEL WITH WIDESPREAD DISTRIBUTION IN THE BRAIN

There is strong evidence that ATP acts as an excitatory neurotransmitt er in the periphery, yet little is known about fast central ATP-mediat ed transmission. We report here the molecular cloning of a novel neuro nal ionotropic ATP receptor of the P-2x subtype (P-2x3) isolated from rat brain. This central P-2x channel subunit has significant amino aci d homology with two recently cloned ATP-gated channels from rat smooth muscle (47%) and pheochromocytoma PC12 cells (37%). P-2x3 receptor co ntains the characteristic 10 conserved cysteines of ATP-gated channels , a putative extracellular region homologous to the Walker type A moti f found in various nucleotide-binding proteins, and two potential site s for phosphorylation by protein kinase C. Homomeric receptor P-2x3 ch annels expressed in Xenopus oocytes produce rapid cation-selective pur inergic currents that are potentiated by zinc ions and reversibly bloc ked by the P-2x antagonists suramin, Reactive Blue 2, and pyridoxalpho sphate-6-axophenyl-2U,4U-disulfonic acid. P-2x3-receptor subunit mRNA is found in the Purkinje cells and the granule cells of the cerebellum as well as in CA3 pyramidal cells of the hippocampus that are innerva ted by zinc-rich axon terminals of messy fibers, Our results suggest t hat fast excitatory synaptic transmission mediated by zinc-sensitive A TP-gated channels is widespread in mammalian brain.