Part:BBa_K5267002

Mammalian MT2 melatonin receptor

The mammalian MT2 melatonin receptor is a G protein-coupled receptor (GPCR) primarily coupled to the Gi/o protein family. This receptor plays a crucial role in regulating circadian rhythms and sleep-wake cycles by responding to melatonin, a hormone produced by the pineal gland. The MT2 receptor has a seven-transmembrane domain structure characteristic of GPCRs and is involved in inhibiting adenylate cyclase activity, leading to decreased levels of cAMP. It also participates in other signaling pathways, including the activation of ERK/MAPK pathway. Structural studies of MT2 reveal unique features such as a "lid-like" structure in the extracellular loop 2 (ECL2) that influences ligand binding and selectivity. This part is essential for projects involving the study of circadian biology, sleep regulation, and the pharmacological targeting of melatonin receptors.

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: GPCRs

Usage and Biology

This part of gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor, a rhodopsin-like class A receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is resadily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin.[1]

In the human body, melatonin (N-acetyl-5-methoxytryptamine) is a widespread neurohormone with roles in circadian rhythm regulation, antioxidative protection and several other functions. It binds to the ligand binding pocket of melatonin receptor with high affinity in the human body.[2]

Figure: Overall structures of MT2 (F: inactive state [PDB ID: 6ME6], J: 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]). (G) Ligand binding site of crystal structures of MT 2 (left: [PDB ID: 6ME6], right: [PDB ID: 6ME9]). (K) Ligand binding site of cryo‐EM structure of MT2 [PDB ID: 7VH0]. [3]

Signal transduction features

As a class of GPCR, MT2 mainly transmits signals through G protein coupling. MT2 regulates the activities of protein kinase A (PKA) and cAMP response element-binding protein by activating Gαi/oA, inhibiting the intracellular AC activity and reducing the intracellular cAMP concentration. MT2 also inhibits the activity of guanylyl cyclase (GC) and reducing the intracellular cGMP concentration, to regulate cGMP-dependent signaling pathways. MT2 can also regulate gene expression by coupling with Gαq/11 protein to activate PLC, increase intracellular Ca2+ level, and activate PKC pathway to promote downstream signal transduction. [4]
In terms of transcriptional regulation, melatonin signaling typically inhibits cAMP-responsive element binding (CREB), which activates gene transcription though the ERK pathway. [3]
The figure from Okamoto, H. H., Cecon, E., Nureki, O., Rivara, S., & Jockers, R. (2024) shows melatonin receptor-mediated signal transduction. (Fig.1)

Figure 1. Melatonin receptor signaling pathways. [3]

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.