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Melatonin desensitizes endogenous MT₂ melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin

MATTHEW J. GERDIN^*,,, MONICA I. MASANA^*, MOISÉS A. RIVERA-BERMÚDEZ^*, RANDALL L. HUDSON^||, DAVID J. EARNEST, MARTHA U. GILLETTE and MARGARITA L. DUBOCOVICH^*,,,,1

^* Department of Molecular Pharmacology and Biological Chemistry,
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine;
Northwestern University Institute for Neuroscience,
Drug Discovery Program, Northwestern University, Chicago, Illinois, USA;
^|| Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA;
Department of Human Anatomy and Medical Neurobiology, Texas A&M University Health Science Center, College Station, Texas, USA; and
Department of Cell and Structural Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA

¹Correspondence: Department of Molecular Pharmacology and Biological Chemistry (S215), Northwestern University Feinberg School of Medicine, 303 East Chicago Ave., Chicago, IL 60611-3008, USA. E-mail: mdubo{at}northwestern.edu

The hormone melatonin phase shifts circadian rhythms generated by the mammalian biological clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, through activation of G protein-coupled MT₂ melatonin receptors. This study demonstrated that pretreatment with physiological concentrations of melatonin (30–300 pM or 7–70 pg/mL) decreased the number of hMT₂ melatonin receptors heterologously expressed in mammalian cells in a time and concentration-dependent manner. Furthermore, hMT₂-GFP melatonin receptors heterologously expressed in immortalized SCN2.2 cells or in non-neuronal mammalian cells were internalized upon pretreatment with both physiological (300 pM or 70 pg/mL) and supraphysiological (10 nM or 2.3 ng/mL) concentrations of melatonin. The decrease in MT₂ melatonin receptor number induced by melatonin (300 pM for 1 h) was reversible and reached almost full recovery after 8 h; however, after treatment with 10 nM melatonin full recovery was not attained even after 24 h. This recovery process was partially protein synthesis dependent. Furthermore, exposure to physiological concentrations of melatonin (300 pM) for a time mimicking the nocturnal surge (8 h) desensitized functional responses mediated through melatonin activation of endogenous MT₂ receptors, i.e., stimulation of protein kinase C (PKC) in immortalized SCN2.2 cells and phase shifts of circadian rhythms of neuronal firing in the rat SCN brain slice. We conclude that in vivo the nightly secretion of melatonin desensitizes endogenous MT₂ melatonin receptors in the mammalian SCN thereby providing a temporally integrated profile of sensitivity of the mammalian biological clock to a melatonin signal.—Gerdin, M. J., Masana, M. I., Rivera-Bermúdez, M. A., Hudson, R. L., Earnest, D. J., Gillette, M. U., Dubocovich, M. L. Melatonin desensitizes endogenous MT₂ melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin.

Key Words: desensitization • internalization • protein kinase C • SCN2.2 cells • circadian rhythms