Intracellular cross talk and physical interaction between two classes of neurotransmitter-gated channels

Fast chemical communications in the nervous system are mediated by several classes of receptor channels believed to be independent functionally and physically. We show here that concurrent activation of P2X 2 ATP-gated channels and 5-HT 3 serotonin-gated channels leads to functional interaction and nonadditive currents (47-73% of the predicted sum) in mammalian myenteric neurons as well as in Xenopus oocytes or transfected human embryonic kidney (HEK) 293 cell heterologous systems. We also show that these two cation channels coimmunoprecipitate constitutively and are associated in clusters. In heterologous systems, the inhibitory cross talk between P2X 2 and 5-HT 3 receptors is disrupted when the intracellular C-terminal domain of the P2X 2 receptor subunit is deleted and when minigenes coding for P2X 2 or 5-HT 3 A receptor subunit cytoplasmic domains are overexpressed. Injection of fusion proteins containing the C-terminal domain of P2X 2 receptors in myenteric neurons also disrupts the functional interaction between native P2X 2 and 5-HT 3 receptors. Therefore, activity-dependent intracellular coupling of distinct receptor channels underlies ionotropic cross talks that may significantly contribute to the regulation of neuronal excitability and synaptic plasticity