The first melatonin receptor was cloned from frog skin in 1994 and shortly thereafter two human versions of the receptor, now known as MT1 and MT2, were cloned and characterized. MT1 and MT2 receptors are typical seven membrane-spanning G protein-coupled receptors of 350 and 363 amino acids, respectively. They share about 60% amino acid homology. Functionally, the two types of receptors are distinguished by their affinity for melatonin, that of the MT1 receptor being approximately five-fold greater than that of the MT2 receptor.
Table 1 lists many of the tissues in which the melatonin receptors have been reported, indicating their wide and often overlapping distribution. It should be noted that within tissues composed of many regions or cell types, the cellular distribution of the two receptors may be different. For example, MT1, MT2, or both have been found in more than 100 locations in the mammalian brain. Locations in the brain where MT1 has been identified include the hypothalamus, including the SCN, cerebellum, hippocampus, ventral tegmental area, and substantia nigra; MT2 has been found in the SCN and other areas of the hypothalamus.
Table1. Tissue Distribution of Melatonin Receptors
There is also overlap in the signaling pathways used by the two receptors. There are two primary G-protein coupled pathways used by MT1 and MT2 and, as shown in Figure 1, either receptor is capable of activating either pathway, depending on the cell type. In some cells, the receptor (either MT1 or MT2) is coupled to Gi resulting in the inhibition of adenyl cyclase and decreased cyclic AMP levels. In other cells the receptor is coupled to Gq, activating phospholipase C, the cleavage of phosphoinositol diphosphate to release IP3 to raise intracellular Ca2+ levels and diacylglycerol to activate protein kinase C. Several possible downstream events can follow these initial signals and these, too, vary with cell type, although specific details have not been elucidated in all target cells of melatonin.
Fig1. Membrane signaling by the melatonin receptor. The MT1 and MT2 receptors for melatonin, both G-protein coupled receptors, use one of two signaling pathways, depending on the cell type. On the left is shown the interaction of Gi with adenyl cyclase to decrease cyclic AMP levels and therefore cyclic AMP-dependent protein kinase activity (PKA). On the right is shown the interaction of Gq with phospholipase C (PLC) leading to the cleavage of phosphatidyl inositol diphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). These second messengers stimulate increased intracellular Ca2+ and protein kinase C (PKC), respectively. The downstream effects of these events at the membrane vary with cell type.
Although there are some high affinity agonists for MT1 and MT2 receptors that do not distinguish between the two as well as some that are somewhat selective for each of them, no agonists have yet been identified/synthesized that bind one or the other receptor exclusively. This has hampered developing a clear understanding of the role of each of the receptors in the many tissues in which both are found.
