MT2, also known as MEL1b, is a G-protein-coupled receptor activated by melatonin. Melatonin is a hormone synthesized and released by the pineal gland following a circadian rhythm, and MT2 plays a crucial role in various physiological processes. It is involved in regulating sleep, circadian rhythms, mood, learning and memory, and also has implications in neuroprotection, drug abuse, and cancer [1,3]. MT2 is part of the signaling pathways related to these physiological functions, highlighting its overall biological importance. Genetic models, such as KO/CKO mouse models, are valuable for studying MT2's functions.

In osteoporosis, ovariectomized (OVX) mice showed lower MT2 expression in bone marrow primary osteoclast precursors (OCPs) along with higher reactive oxygen species (ROS) levels. Overexpression of MT2 in OCPs inhibited osteoclastogenesis and ROS production, while knockdown had the opposite effects. The addition of hydrogen peroxide (H2O2) blocked the inhibitory effect of MT2 overexpression, indicating that MT2 inhibits osteoclastogenesis by scavenging ROS in OCPs [2]. In brain cancer, the MT2 antagonist DH97 was used to show that MT2 activation promotes the proliferation of human glioma and medulloblastoma cell lines. Gliomas had an increased mRNA expression of MT2 compared to the normal brain cortex, and the MT1/MT2 expression ratio was a positive prognostic factor. Functional selective drugs that inhibit MT2 exerted anti-tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in glioma stem-like cells [4].

In conclusion, MT2 is a key G-protein-coupled receptor in the melatonin-mediated signaling network. Model-based research, especially using KO/CKO mouse models, has revealed its roles in diseases like osteoporosis and brain cancer. In osteoporosis, it regulates osteoclastogenesis through ROS scavenging, and in brain cancer, it promotes tumor cell proliferation. Understanding MT2's functions provides insights into potential therapeutic strategies for these diseases.

References:

1. Liu, Jiabei, Clough, Shannon J, Hutchinson, Anthony J, Popovska-Gorevski, Marina, Dubocovich, Margarita L. 2015. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. In Annual review of pharmacology and toxicology, 56, 361-83. doi:10.1146/annurev-pharmtox-010814-124742. https://pubmed.ncbi.nlm.nih.gov/26514204/

2. Wei, S, Liu, K, Wu, H, Liu, B, Yang, W. 2024. MT2 INHIBITS OSTEOCLASTOGENESIS BY SCAVENGING ROS. In Acta endocrinologica (Bucharest, Romania : 2005), 19, 447-455. doi:10.4183/aeb.2023.447. https://pubmed.ncbi.nlm.nih.gov/38933247/

3. Boiko, Dmytro I, Shkodina, Anastasiia D, Hasan, Mohammad Mehedi, Baig, Atif Amin, Skrypnikov, Andrii M. 2022. Melatonergic Receptors (Mt1/Mt2) as a Potential Additional Target of Novel Drugs for Depression. In Neurochemical research, 47, 2909-2924. doi:10.1007/s11064-022-03646-5. https://pubmed.ncbi.nlm.nih.gov/35689787/

4. Kinker, G S, Ostrowski, L H, Ribeiro, P A C, Markus, R P, Fernandes, P A C M. 2021. MT1 and MT2 melatonin receptors play opposite roles in brain cancer progression. In Journal of molecular medicine (Berlin, Germany), 99, 289-301. doi:10.1007/s00109-020-02023-5. https://pubmed.ncbi.nlm.nih.gov/33392634/