Melatonin (MEL) plays a central role in the regulation of seasonal cycles and in the control of circadian rhythms in mammals. Functional MEL-sensitive receptors were expressed in Xenopus laevis oocytes following injection of poly (A)+ RNA from rat brain. Administration of 0.1–100 μmol/l MEL to voltage-clamped oocytes (holding potential: −70 mV) elicited oscillatory inward currents (reversal potential: −24 mV) which could be blocked by 9-anthracenecarboxylic acid and caffeine. After preincubation with pertussis toxin (PTX) the MEL response disappeared. The expressed MEL-sensitive receptor probably activates Ca2+-dependent chloride currents via a PTX-sensitive G protein and the phosphoinositol pathway.