Difference between revisions of "Part:BBa K5267002"
 
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===Usage and Biology===
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__NOTOC__
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MT2(melatonin receptor type 2) is an integral membrane protein that is a G protein coupled receptor (GPCR), 7-transmembrane receptor. It is found primarily in the retina and brain. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin.[1]
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<partinfo>BBa_K5267002 short</partinfo>
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MT2 has been reported to modulate many physiological processes, especially those related to sleep and circadian rhythm regulation, but also in retina physiology, pain and neuronal and immune functions.
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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]
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===Signal transduction features===
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<p> 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. </p>
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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. [2]
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In terms of transcriptional regulation, melatonin signaling typically inhibits cAMP-responsive element binding (CREB), which activates gene transcription though the ERK pathway. [3]
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The figure from Okamoto, H. H., Cecon, E., Nureki, O., Rivara, S., & Jockers, R. (2024) shows melatonin receptor-mediated signal transduction. (Fig.1)  
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Figure 1. Melatonin receptor signaling pathways. [3]
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===References===
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[1] R. Jockers et al., “Update on melatonin receptors: IUPHAR Review 20,” Br. J. Pharmacol., vol. 173, no. 18, pp. 2702–2725, Sep. 2016, doi: 10.1111/bph.13536.
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[2] “Melatonin receptor structure and signaling,” J. Pineal Res., vol. 76, no. 3, p. e12952, Apr. 2024, doi: 10.1111/jpi.12952.
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==Sequence and Features==
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<partinfo>BBa_K5267002 SequenceAndFeatures</partinfo>
  
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[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.
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<!-- Uncomment this to enable Functional Parameter display
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===Functional Parameters===
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<partinfo>BBa_K5267002 parameters</partinfo>
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==Profile==
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Name: MTNR1B
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<br>Pairs: 1089bp
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<br>Origin: Homo sapiens
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<br>Properties: GPCRs
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==Usage and Biology==
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<p> 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] </p>
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<p> 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] </p>
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<html>
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<figure class="figure">
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<div style="width=100%; height=auto; text-align: center">
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<img src="https://static.igem.wiki/teams/5267/runtimeerror/mtnr1b-1.png" class="figure-img img-fluid rounded"  height="800px">
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</div>
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</figure>
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</html>
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<p> 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] </p>
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==Signal transduction features==
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<p> 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] </p>
 +
<p> In terms of transcriptional regulation, melatonin signaling typically inhibits cAMP-responsive element binding (CREB), which activates gene transcription though the ERK pathway. [3] </p>
 +
<p> The figure from Okamoto, H. H., Cecon, E., Nureki, O., Rivara, S., & Jockers, R. (2024) shows melatonin receptor-mediated signal transduction. (Figure.1)  </p>
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 +
<html>
 +
 
 +
<figure class="figure">
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<div style="width=100%; height=auto; text-align: center">
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<img src="https://static.igem.wiki/teams/5267/runtimeerror/vetsci-09-00309-g002.png" class="figure-img img-fluid rounded"  height="700px">
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</div>
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</figure>
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</html>
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<p> Figure 2. Melatonin receptor signaling pathways [3]. </p>
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==Reference==
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<p> [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. </p>
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<p> [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. </p>
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<p> [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. </p>
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<p> [4] “Melatonin receptor structure and signaling,” J. Pineal Res., vol. 76, no. 3, p. e12952, Apr. 2024, doi: 10.1111/jpi.12952. </p>

Latest revision as of 17:03, 30 September 2024

Mammalian MT2 melatonin receptor, Gi-coupled GPCR.

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 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]


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. (Figure.1)

Figure 2. 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.