MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective

Abstract

Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.

Keywords: cancer; circadian rhythm disorders; depression; drugs of abuse; neuroprotection; sleep disorders.

Figures

Figure 1

Therapeutic implications of exogenous melatonin. Melatonin production in the pineal gland and locally in the retina follows a circadian rhythm, with the highest levels produced during the dark phase. The rhythmic production of melatonin is controlled by endogenous circadian oscillations and entrained by the light-dark cycle with a 24-h period. Pineal melatonin activates MT1 and MT2 melatonin receptors in the SCN, discrete brain areas, and peripheral tissues to signal photoperiodic information and regulate physiological functions. Exogenous melatonin modulates processes and responses in the central nervous system via activation of the MT1 and/or MT2 melatonin receptors. Further melatonin activation of MT1 receptors decreases breast and prostate cancer cell growth. Abbreviation: SCN, suprachiasmatic nucleus.

Figure 2

Melatonin receptor signaling. (a) MT1 or MT2 monomeric receptor signaling. Both MT1 and MT2 melatonin receptors couple to pertussis toxin–sensitive Gαi, β, γand –insensitive Gq, β, and γproteins, inhibiting forskolin-stimulated cAMP, protein kinase A signaling, and CREB phosphorylation (see Reference 3). (b) MT1/MT2 heterodimer receptor signaling. Human MT1 and MT2 receptors form homo- and hetero-oligomers between themselves, altering the pharmacological properties of the individual receptors. Formation densities of the MT1/MT2 heterodimer and the MT2/MT2 homodimer are similar and 3- to 4-fold lower than the MT1/MT1 homodimer. Native functional MT1/MT2 heterodimers have been characterized in mouse rod photoreceptors, where they mediate the enhancement of scotopic light sensitivity by melatonin through a heterodimer-specific PLC and PKC pathway (21). Abbreviations: AC, adenylyl cyclase; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C. Figure modified with permission from Reference .