We have used the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel as a model system to study the cAMP signal transduction pathways coupled to the Xenopus melatonin receptor. During forskolin (Fsk) stimulation, melatonin reduced the amplitude of the CFTR currents in oocytes injected with in vitro transcribed cRNAs for the Xenopus melatonin receptor and CFTR. Pertussis toxin (Ptx) treatment eliminated melatonin inhibition of Fsk stimulated CFTR currents. In oocytes injected with cRNA for melatonin receptors, serotonin receptors (5-HT7), and CFTR Cl- channels, application of melatonin together with serotonin (5-HT) activated an additional inward current showing potentiation of adenylyl cyclases by melatonin receptors. Subthreshold activation of 5-HT7 receptors was sufficient and necessary to permit activation of CFTR channels by melatonin. Preexposure to melatonin desensitized the melatonin receptor mediated response. Therefore, based on this model system, the effects of melatonin in vivo could be either positive or negative modulation of other neuronal inputs, depending on the mode of adenylyl cyclase stimulation.
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