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The hormone melatonin is produced and secreted from the pineal gland following a circadian rhythm with high levels at night. It has been shown to regulate the body clock and to affect a variety of physiological and neuroendocrine functions. Our long term goal is to understand the function, signaling pathways and molecular properties of melatonin receptor subtypes and the role of melatonin in regulating cardiovascular, visual and circadian function.
Membrane associated melatonin receptors[MT1,MT2,MT3] are members of the G protein linked receptor family. They couple to inhibition of adenylate cyclase and other signaling pathways, and are involved in the regulation of circadian rhythms, visual cardiovascular and neuroendocrine function and seasonal reproduction. The putative MT3 subtype couples to stimulation of phosphoinsitide hydrolysis, however, its function is till unknown. Melatonin also acts at putative cytosolic and nuclear melatonin receptors to mediate a variety of cellular effects, which may contribute to its oncostatic, immunological, and antiaging effects of this hormone.
In order to unravel the mechanism(s) of action of melatonin, it is necessary to determine its sites of action, the molecular and functional relationships of the subtypes and to relate these findings to the in vivo effects of the hormone. Ongoing studies towards these goals focus on the localization and characterization of melatonin receptor subtypes, cloning, characterization and regulation of melatonin receptors (by the light/dark cycle, melatonin, and neural activity), modulation of signal transduction pathways through activation of melatonin receptor subtypes, role of retinal dopamine-melatonin interactions in transmitting light information to the brain, and the involvement of melatonin receptors in the retina and the circadian pacemaker in the regulation of visual function and circadian rhythms of behavior.
Additional studies include the use of molecular based drug design to discover novel agonists and antagonists with selectivity for the different melatonin receptor subtypes. These molecules may have therapeutic potential to treat human circadian rhythms disturbances such as mood and sleep disorders of endogenous (blindness, aging, delay sleep phase syndrome) and exogenous (jet lag, phase shift) causes, cardiovascular disease, cancer and aging.
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Signal Transduction
Benloucif, S., Masana, M.I., Zee, P.C., and Dubocovich, M.L.
Nimodipine potentiates light-induced phase shifts of circadian activity rhythms but not c-fos expression in the SCN of mice.
Brain Res. 966: 157-161,2003
Gerdin, M.J., Masana, M.I., Ren, D., Miller, R.J., and Dubocovich, M.L.
Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 melatonin receptors.
J. Pharmacol. Exp. Ther., 304: 931-939, 2003.
Gerdin, M.J., Mseeh, F. and Dubocovich, M.L.
Mutagenesis studies of the human MT2 melatonin receptor: a challenge to proposed ligand binding models.
Biochem Pharmacol. 66: 315-320, 2003.
Rivera-Bermudez, M.A., Gerdin, M.A., Earnest, D.J., and Dubocovich, M.L.
Rugulation of basal rhythmicity in protein kinase C activity by melatonin in immortalized rat suprachiasmatic nucleus cells. Neuroscience Letters 346: 37-40, 2003.
Rivera-Bermudez, M.A., Masana, M.I, Brown, G.M., Earnest, D.J., and Dubocovich, M.L.
Immortalized Cells From the Rat Suprachiasmatic Nucleus Express Functional Melatonin Receptors.
Brain Res. (In press), 2004.
PubMed Reference Lookup
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