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 are classified into the ML1 and ML2 categories. Melatonin receptor showing the general pharmacology of the ML1 subtype [mt1 (former MEL1a), MT2 (former MEL1b)] are members of the G protein-linked receptor family. They couple to inhibition of adenylate cyclase and other signalling pathways, and are involved in the regulation of circadian rhythms, visual and cardiovascular function and seasonal reproduction. The putative ML2 subtype couples to stimulation of phosphoinositide hydrolysis, however, its function is still 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.

Selected recent publications

• Hunt, A.E. Al-Ghoul, W., Gillette, M.U. and Dubocovich, M. L. (2001).The MT2 melatonin receptor mediates phase advances of the rat suprachiasmatic circadian clock. Am.J. Physiol. 280: C110-C118.

• Reid, K. J., Chang, A., Dubocovich, M.L. (in press). Turek, F.W., Takahashi, J.S., Zee, P.C. Familial advance sleep phase syndrome. Arch. Neurology.

• Masana, M.I., Benloucif, S. and Dubocovich, M.L. (2000). Diurnal and circadian rhythms of mt1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H.HeN mice. J. Pineal Res. 28: 185-192.

• Ruby, N. F., Dubocovich, M.L. and Heller, H.C. (2000). Melatonin is suppressed in siberian hamsters that fail to reentrain to the photocycle. Am. J. Physiol. 278: R757-R762.

• Rosenstein, R.E. and Dubocovich, M.L.: (in press). Characterization of 2-[125I]-Iodomelatonin binding sites in the golden hamster retina by autoradiograhpy. Biol. Rhythm Res.

• Benloucif, S., Masana, M.I., YUN, K. and Dubocovich, M.L. (1999). Interactions between light and melatonin on the circadian clock of mice. J. Biol. Rhythms 14:281-289.

• Benlouicf, S., Bauer, G.L. Dubocovich, M.L., Finkel, S.I. and Zee, P.C.(1999). Nimodipine potentiates the light-induced suppression of melatonin in humans. Neurosci. Lett. 272:67-71.
  

• Masana, M.I., Witt-Enderby, P.A. and Dubocovich, M.L. (1999). Physiological exosure to melatonin modulates the density of the human mt1 melatonin receptor expresion in CHO cells. J. Nuerochemistry, (accepted with revisions).
  

• Dubocovich, M.L., YUN, K., AL-GHOUL, W., BENLOUCIF, S. and MASANA, M.I. (1998). Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J.12:1211-1220.
  

• AL-GHOUL, W.M., HERMAN, M.D. and Dubocovich, M.L. (1998). Melatonin receptor subtype (mt1 and MT2) expression in human cerebellum. NeuroReport 9: 4063-4068.
  

• Witt-Enderby, P.A., Masana, M.I. and Dubocovich, M.L. (1998). Physiological exposure to melatonin supersensitizes the cyclic AMP-dependent signal transduction cascade in CHO cells expressing the human mt₁ melatonin receptor. Endocrinology 139: 3064-3071.
  

• Doolen, S., Krause, D.N., Dubocovich, M.L. and Duckles, S.P. (1998). Melatonin mediates two distinct responses in vascular smooth muscle. European Journal Pharmacology 345: 67-69.
  

• Beresford, I.J.M., Browning, C., Starkey, S.J., Brown, J., Foord, S.M., Coughlan, J., North, P.C., Dubocovich, M.L. and Hagan, R.M. (1998). GR 196429: A non-indolic agonist at high affinity melatonin1 receptors. Journal Pharmacology Experimental Therapeutics 285: 1239-1245.
  

• Dubocovich, M.L., Masana, M.I., Iacob, S. and Sauri, D. (1997). Melatonin receptor antagonists differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn Schmiederberg’s Archives Pharmacology 355: 365-375.
  

• Benloucif, S., Masana, M.I. and Dubocovich, M.L. (1997). Responsiveness to melatonin and its receptor expression in the aging circadian clock of mice. American Journal of Physiology 273: R1855-R1860.

• Benloucif, S., Masana, M.I. and Dubocovich, M.L. (1997). Light-induced phase shifts of circadian activity rhythms and immediate early gene expression in the suprachiasmatic nucleus are attenuated in old C3H/HeN mice. Brain Research 747: 34-42.
  

• Witt-Enderby, P.A. and Dubocovich, M.L. (1996). Characterization and regulation of the human ML1A melatonin receptor stably expressed in chinese hamster ovary cells. Molecular Pharmacology 50: 166-174.
  

• Jansen, J.M., Copinga, S., Gruppen, G., Molinari, E.J., Dubocovich, M.L. and Grol, C.J. (1996). The high affinity melatonin binding site probed with conformationally restricted ligands-I. Pharmacophore and minireceptor models. Bioorg. Medicinal Chemistry 4:1321-1332.
  

• Benloucif, S. and Dubocovich, M. L.. (1996). Melatonin and light induce phase shifts of circadian rhythms in the C3H/HeN mouse. Journal of Biological Rhythms 11:113-125.
  

• Dubocovich, M. L., Benloucif, S. and Masana, M.I. (1996). Melatonin receptors in the mammalian suprachiasmatic nucleus. Behavioral Brain Research 73:141-147.
  

• Larson-Pryor, L., Siuciak, J.A. and Dubocovich, M.L. (1996). Localization of 2-[125I]-iodomelatonin binding sites in visual areas of the turtle brain. European Journal of Pharmacology 297: 181-185.
  

• Molinari, E.J., North, P.C. and Dubocovich, M.L. (1996). 2-[125I]-iodo-5-methoxycarbonylamino-N-acetyltryptamine: a selective radioligand for characterization of melatonin ML2 binding sites. European Journal of Pharmacology 301: 159-168.
  

• Masana, M.I., Benloucif, S. and Dubocovich, M.L. (1996). Light-induced c-fos mRNA expression in the suprachiasmatic nucleus and the retina of C3H/HeN mice. Molecular Brain Research 42:193-201.
  

• Benloucif, S., and Dubocovich, M.L. (1996) Phase response curves to light and to melatonin in the C3H/HeN mouse. Journal of Biological Rhythms, 11:113125.
  

• Witt-Enderby, P.A. and Dubocovich, M. L. (1996). Characterization and regulation of the human ML1A melatonin receptor stably expressed in CHO cells. Molecular Pharmacology 50: 166-174.
  

• Dubocovich, M.L., Krause, D.N., Iacob, S., Benloucif, S., and Masana, M.I. (1995) Localization and physiological role of melatonin receptors in the visual and circadian systems in F. frashicni, R.J. Reiter and B. stankov (Eds), The Pineal Gland and Its Hormones: Fundamental and Clinical Perspectives pp. 61-74 New York: Plenum.
  

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