Melatonin receptor is a G protein-coupled receptor (GPCR) which binds melatonin. Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and birds. The MT1 subtype's expression in the pars tuberalis of the pituitary gland and suprachiamatic nuclei of the hypothalamus is indicative of melatonin's circadian and reproductive functional involvement. The MT2 subtype's expression in the retina is suggestive of melatonin's effect on the mammalian retina occurring through this receptor.
Melatonin (5-methoxy-N-acetyltryptamine) is primarily synthesized in the pineal gland and retina with high levels at night time. Melatonin has been known for many years to entrain circadian rhythms and regulate seasonal reproduction. Recent studies have expanded the list of functions of melatonin to include modulation of cardiac events, regulation of cancer progress and involvement in neurogenesis and diabetes.
Melatonin mediates its effects through a variety of mechanisms including 1) binding to high affinity G-protein coupled MT1 and MT2 melatonin receptors; 2) binding to other binding sites including the MT3 binding site, calmodulin, calreticulin and human plasma albumin; 3) acting as an antioxidant.
With evolving understanding of melatonin and its receptors, scientists start to appreciate the functional and therapeutic values of this hormone and regard it as a potential therapeutic target of treating jet leg, sleep disorder, neurodegenerative diseases, depression and drug addiction. Drugs that activate the MT1 and MT2 melatonin receptors have been discovered and brought to the market for therapeutic usages. So far, there are three drugs available. Agomelatine, a MT1/MT2 melatonin receptors agonist and 5-HT2c antagonist, is used for treating major depressive disorder. Ramelteon, a MT1/MT2 melatonin receptors agonist, is for insomnia and circadian sleep disorder. Circadin, a prolonged-release melatonin formulation, is for improving sleep quality.
Attempts to localize the expression of melatonin receptor subtypes were mostly done by using reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization techniques. MT1 and MT2 melatonin receptor mRNA has been found in both neuronal and peripheral tissues. In central nervous system, MT1 and MT2 melatonin receptor mRNA was found in human cerebellum, occipital cortex, parietal cortex, temporal cortex, thalamus, frontal cortex, hippocampus, suprachiasmatic nucleus (SCN) and retina. MT1 and MT2 melatonin receptor mRNA have also been found in fetal kidney, granulose cells, and coronary arteries.
Wide distribution of MT1 and MT2 melatonin receptors indicates their versatile actions in both central nervous system and peripheral organs. In addition, the overlapping expression of the MT1 and MT2 melatonin receptors suggests the various patterns of interactions between these two receptors including subtype specific functions, antagonistic and synergistic effects. For instance, MT1 and MT2 melatonin receptors exert distinct effects and show subtype specific actions in the SCN slice preparation with MT1 melatonin receptor inhibiting neuronal firing, while MT2 phase shifting the peak of neuronal firing. In addition, both MT1 and MT2 receptors are expressed in the eye while only the MT1 involved in regulating intraocular pressure. Antagonistic effects are observed between MT1 and MT2 melatonin receptors in vasculature smooth muscle, where the activation of MT1 receptors leads to constriction and MT2 receptors leads to dilation. It is likely that co-expression of the MT1 with MT2 melatonin receptors maintains a balance of vascular tone within the system. Formation of oligomer of MT1 and MT2 melatonin receptors suggests a possible synergistic action of these two receptors. It has been documented that heterodimers of MT1 and MT2 melatonin receptors show a distinct pharmacological profile from monomers and homo-dimers, although functional consequences and localization of homo- and heterooligomers await further investigation.
MT1 and MT2 melatonin receptors can be pharmacologically distinguished by using melatonin receptor partial agonists and antagonists. Dubocovich et al. (1997) showed while significant correlation of affinity constants of melatonin receptor agonists was observed between MT1 and MT2 melatonin receptors, there was no correlation of pKi values between these two receptor subtypes using melatonin receptor partial agonists and antagonists.
Wang, L. (2012). Novel Melatonin Binding Site on the TrkB Receptor. State University of New York at Buffalo.