Chemical synapses use small molecule transmitters and neuropetides for transmission. It is textbook knowledge that only small molecule neurotransmitters directly gate ion channels, mediating fast neurotransmission, whereas neuropeptides activate exclusively G-protein coupled receptors, mediating slow neurotransmission. Cnidaria are animals with a simple body plan; nervous systems probably appeared in animals similar to Cnidarians. We used a model Cnidarian, Hydra magnipapillata, to isolate cDNAs for ion channel subunits. Upon expression of a specific combination of these subunits in Xenopus oocytes, neuropeptides rapidly activated a current that could not be elicited in oocytes not expressing the channel subunits; these neuropeptides had been previously isolated from neurons of Hydra. Using in situ hybridization, we located the channel- expressing cells adjacent to the peptide-expressing neurons, suggesting that the peptides are the natural ligands for this channel. Our results show that the simple nervous systems of Hydra uses neuropeptides for fast neurotransmission, suggesting that neuropeptides were among the first ligands for ion channels. Orphan ion channel receptors that are closely related to the Hydra channel exits also in mammals; they are candidates for channels directly gated by yet to be identified neuropeptides.