Part:BBa_K5267002

Mammalian MT2 melatonin receptor

The mammalian MT2 melatonin receptor is classified as a G protein-coupled receptor (GPCR) and plays a crucial role in regulating circadian rhythms and sleep-wake cycles by responding to melatonin, a hormone produced by the pineal gland.Notably, the melatonin receptors MT1 and MT2 exhibit variations in the conformational attributes of specific secondary structural components, particularly within the helical regions and loop domains. A significant example of this is the second extracellular loop (ECL2), whose conformation differs markedly between the two receptor isoforms. This divergence in ECL2 is thought to be a pivotal factor contributing to the differential ability of MT1 to engage downstream Gq/11 proteins, a functional characteristic that MT2 lacks. Such structural disparities are believed to manifest in the distinct functional repertoires of MT1 and MT2, underscoring the importance of these subtle conformational variations in dictating receptor functionality.

Upon activation by melatonin, the MT2 receptor triggers several intracellular signaling pathways, including the cAMP-PKA pathway and the cGMP-PKG signaling pathway. These pathways influence gene expression related to various cellular processes, such as metabolism, growth, and apoptosi

Sequence and Features

Assembly Compatibility:

• 10
  COMPATIBLE WITH RFC[10]
• 12
  COMPATIBLE WITH RFC[12]
• 21
  COMPATIBLE WITH RFC[21]
• 23
  COMPATIBLE WITH RFC[23]
• 25
  COMPATIBLE WITH RFC[25]
• 1000
  COMPATIBLE WITH RFC[1000]

Profile

Name: MTNR1B
Pairs: 1089bp
Origin: Homo sapiens
Properties: A GPCR that responds to melatonin
Short description: MTNR1B
Full description: The part encodes a 7-transmembrane melatonin receptor MTNR1B, which responses to melatonin.

Usage and Biology

MT2 (melatonin receptor type 2) is an integral membrane protein classified as a G protein-coupled receptor (GPCR) and features a seven-transmembrane domain structure. It is predominantly located in the retina and brain, where it is believed to participate in light-dependent functions within the retina and may be involved in the neurobiological effects of melatonin.[1]

Unlike the distribution of MT1, MT2 is primarily found in brain regions that regulate non-rapid eye movement (NREM) sleep, such as the reticular nucleus of the thalamus, as well as in areas that control sleep homeostasis, including the cortex and the ventrolateral preoptic nucleus (VLPO).

In the human body, melatonin (N-acetyl-5-methoxytryptamine) is a widespread neurohormone with roles in the regulation of circadian rhythms, antioxidative protection, and various other functions. Melatonin binds with high affinity to the ligand-binding pocket of melatonin receptors, including MT2. This binding event activates downstream signaling pathways that influence gene expression related to various cellular processes[2].

The figure from Okamoto, H. H. (2024) illustrates the overall structure of MT2 in both its activated and inactivated forms. It also shows the position of the ligand-binding pocket of MT2, where melatonin binds to initiate receptor activation and subsequent downstream signaling[2].

Figure 1: Overall structures of MT2 (A: inactive state [PDB ID: 6ME6], D: active state [PDB ID: 7VH0]). Overall TM6 movement during receptor activation of MT 2(inactive state: [PDB ID: 6ME9] and active state: [PDB ID: 7VH0]). (B) Ligand binding site of crystal structures of MT 2 (left: [PDB ID: 6ME6], right: [PDB ID: 6ME9]). (C) Overall TM6 movement during receptor activation of MT2 (inactive state: [PDB ID: 6ME9] and active state: [PDB ID: 7VH0]). (F) Ligand binding site of cryo‐EM structure of MT2 [PDB ID: 7VH0]. [3]

As a member of the GPCR family, MT2 primarily transmits signals through G protein coupling. Specifically, MT2 regulates the activities of protein kinase A (PKA) and cAMP response element-binding protein (CREB) by activating Gαi/o proteins, which inhibit intracellular adenylyl cyclase (AC) activity and reduce intracellular cAMP concentration. Additionally, MT2 inhibits the activity of guanylyl cyclase (GC), thereby decreasing intracellular cGMP concentration and regulating cGMP-dependent signaling pathways. Furthermore, MT2 can regulate gene expression by coupling with Gαq/11 proteins to activate phospholipase C (PLC), increase intracellular Ca²⁺ levels, and activate the protein kinase C (PKC) pathway, promoting downstream signal transduction.[4].The figure from Okamoto, H. H (2024) depicts melatonin receptor-mediated signal transduction.

Figure 2. Melatonin receptor signaling pathways [4].

Reference

[1] N. database, "Gene [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004 – [cited 2024 Sep 01]. Available from: https://www.ncbi.nlm.nih.gov/gene/," 2004.

[2] H. H. Okamoto, E. Cecon, O. Nureki, S. Rivara, and R. Jockers, “Melatonin receptor structure and signaling,” Journal of Pineal Research, vol. 76, no. 3, 2024.

[3] Y. Gao, S. Zhao, Y. Zhang, and Q. Zhang, “Melatonin Receptors: A Key Mediator in Animal Reproduction,” Vet. Sci., vol. 9, no. 7, p. 309, Jun. 2022, doi: 10.3390/vetsci9070309.

[4] “Melatonin receptor structure and signaling,” J. Pineal Res., vol. 76, no. 3, p. e12952, Apr. 2024, doi: 10.1111/jpi.12952.