The pineal hormone melatonin elicits potent circadian and reproductive effects in mammals through high-affinity guanine nucleotide binding protein (G protein)-coupled receptors. Two melatonin receptor subtypes have been cloned from mammals and designated Mel1a and Mel1b receptors. A biological clock in the suprachiasmatic nuclei (SCN) is responsible for generating and controlling the melatonin rhythm in mammals. Melatonin elicits two distinct actions in the SCN, the acute inhibition of neuronal activity and phase shifting. Both Mel1a and Mel1b gene expressions have been found in the SCN. Targeted disruption of the Mel1a receptor only eliminates the acute inhibitory effect of melatonin on neuronal firing, yet the melatonin-mediated phase shifts are only modestly altered in the Mel1a receptor-deficient mice. Because pertussis toxin still blocks melatonin-induced phase shifts in the Mel1a knockout mice, and the only known receptor subtype expressed in the SCN of Mel1a receptor-deficient mice is the Mel1b receptor, we hypothesize that both Mel1a and Mel1b are involved in mediating the effect of melatonin in the SCN. We have cloned the mouse Mel1b receptor gene, and the generation of Mel1b knockout mice is also underway. Here we propose to characterize the mouse Mel1b receptor pharmacologically and functionally. We also plan to perform electrophysiology and behavior studies with the Mel1b knockout and Mel1a/Mel1b double knockout mice. Our studies will provide valuable insight into the molecular mechanisms underlying the circadian action of melatonin in the mammalian SCN.
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