Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways

Pandi-Perumal, Seithikurippu R.; Trakht, Ilya; Srinivasan, V.; Spence, D. Warren; Maestroni, Georges J. M.; Zisapel, Nava; Cardinali, Daniel P.

doi:10.1016/j.pneurobio.2008.04.001

Cited by 665 publications

(552 citation statements)

References 339 publications

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“…Melatonin is evolutionary conserved and exerts many regulatory functions by modulating cellular behavior via binding to specific receptors and intracellular targets (Figure 2) [9,10].…”

Section: Melatonin Synthesis and Its Targetsmentioning

confidence: 99%

Melatonin: A pleiotropic molecule regulating inflammation

Radogna

Diederich

Ghibelli

2010

Biochemical Pharmacology

308

247

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Melatonin is a neurohormone produced by the pineal gland that regulates sleep and circadian functions. Melatonin also regulates inflammatory and immune processes acting as both an activator and inhibitor of these responses. Melatonin demonstrates endocrine, but also paracrine and autocrine effects in the leukocyte compartment: on one side, leukocytes respond to melatonin in a circadian fashion; on the other side, leukocytes are able to synthesize melatonin by themselves.With its endocrine and paracrine effects, melatonin differentially modulates pro-inflammatory enzymes, controls production of inflammatory mediators such as cytokines and leukotrienes and regulates the lifespan of leukocytes by interfering with apoptotic processes. Moreover, its potent anti-oxidant ability allows scavenging of oxidative stress in the inflamed tissues. The interesting timing of pro-and anti-inflammatory effects, such as those affecting lipoxygenase activity, suggests that melatonin might promote early phases of inflammation on one hand and contribute to its attenuation on the other hand, in order to avoid complications of chronic inflammation. This review aims at giving a comprehensive overview of the various inflammatory pathways regulated by this pleiotropic hormone.

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“…Melatonin is evolutionary conserved and exerts many regulatory functions by modulating cellular behavior via binding to specific receptors and intracellular targets (Figure 2) [9,10].…”

Section: Melatonin Synthesis and Its Targetsmentioning

confidence: 99%

Melatonin: A pleiotropic molecule regulating inflammation

Radogna

Diederich

Ghibelli

2010

Biochemical Pharmacology

308

247

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“…7 Loss of the MT2 receptor and decreased levels of melatonin have been reported in brains of anxiety disorders and Alzheimer's disease, while an impairment of learning and memory has also been observed in MT2 receptor knockout mice, 12 it is therefore conceivable that the MT2 receptor must have a role in preserving cognitive function. Since axon development and synapse formation have a critical role in learning and memory, we investigated the roles of the MT2 receptor in axonogenesis and synaptic transmission.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…7 The MT2 receptor can form homodimers or heterodimers in response to different stimulations or by interacting with other proteins in the plasma membrane. 7 Activation of the MT2 receptor frequently activates the PI3K/Akt pathway and thus inhibits GSK-3β, the latter is a critical step in the formation of neuronal polarity. 33 Therefore, we measured the activity of Akt and GSK-3β and found that activation of Akt was closely correlated with GSK-3β inhibition when the MT2 receptor was activated; meanwhile, the inhibitory phosphorylation of CRMP-2 was suppressed.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the biological functions of melatonin are mediated by its two receptors, MT1 and MT2 receptors, both of them belong to the G protein-coupled receptor (GPCR) subfamily and are widely expressed throughout the central nervous system (CNS). 7 Activation of the MT2 receptor in response to melatonin is critical for controlling circadian rhythms 7 and regulation of slow wave sleep. 8,9 Early studies have shown that activation of the MT2 receptor in the retina reduces the release of dopamine, while dopamine inhibits growth cone motility and neurite outgrowth during embryonic development, 10,11 suggesting the involvement of the MT2 receptor in functional axonogenesis.…”

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confidence: 99%

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The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling

Man

et al. 2014

Cell Death Differ

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The MT2 receptor is a principal type of G protein-coupled receptor that mainly mediates the effects of melatonin. Deficits of melatonin/MT2 signaling have been found in many neurological disorders, including Alzheimer's disease, the most common cause of dementia in the elderly, suggesting that preservation of the MT2 receptor may be beneficial to these neurological disorders. However, direct evidence linking the MT2 receptor to cognition-related synaptic plasticity remains to be established. Here, we report that the MT2 receptor, but not the MT1 receptor, is essential for axonogenesis both in vitro and in vivo. We find that axon formation is retarded in MT2 receptor knockout mice, MT2-shRNA electroporated brain slices or primary neurons treated with an MT2 receptor selective antagonist. Activation of the MT2 receptor promotes axonogenesis that is associated with an enhancement in excitatory synaptic transmission in central neurons. The signaling components downstream of the MT2 receptor consist of the Akt/GSK-3β/CRMP-2 cascade. The MT2 receptor C-terminal motif binds to Akt directly. Either inhibition of the MT2 receptor or disruption of MT2 receptor-Akt binding reduces axonogenesis and synaptic transmission. Our data suggest that the MT2 receptor activates Akt/GSK-3β/CRMP-2 signaling and is necessary and sufficient to mediate functional axonogenesis and synaptic formation in central neurons. Synaptic circuits are established at the sites of axon-dendritic, axon-somatic or axon-axonal contact, in which functional axonogenesis is a critical step. 1 Axonogenesis can be regulated by many intracellular signals that involve cytoskeletal rearrangements, 2 local protein degradation, 3 as well as diffusional barriers. 4 Additionally, several extracellular neurotrophic factors and hormones have also been shown to have a role in axon guidance and synaptic formation in central neurons. 5,6 To date, the role of melatonin and its receptors in axonogenesis remains unclear. Most of the biological functions of melatonin are mediated by its two receptors, MT1 and MT2 receptors, both of them belong to the G protein-coupled receptor (GPCR) subfamily and are widely expressed throughout the central nervous system (CNS). 7 Activation of the MT2 receptor in response to melatonin is critical for controlling circadian rhythms 7 and regulation of slow wave sleep. 8,9 Early studies have shown that activation of the MT2 receptor in the retina reduces the release of dopamine, while dopamine inhibits growth cone motility and neurite outgrowth during embryonic development, 10,11 suggesting the involvement of the MT2 receptor in functional axonogenesis. In mutant mice with deficient expression of the MT2 gene, the induction of long-term potentiation (LTP) of excitatory synaptic transmission is impaired, and this impairment is closely related to deficits in learning. 12 In the hippocampus, the MT2 receptor inhibits GABA A receptor-mediated current, 13 which is implicated in the synaptic transmission. In Alzheimer's disease, expression of the MT...

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Melatonin binds with high affinity and specificity to beta‐amyloid: LC‐MS provides insight into Alzheimer’s disease treatment

et al. 2021

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To study the potential relationship between melatonin and beta-amyloid (Abeta), we established a liquid chromatography-mass spectrometry (LC-MS) method to quantitatively analyze melatonin, deuterated isotopes (melatonin-D4), and internal standard 6-iodo-2-(4'-dimethylamino-) phenyl-imidazo(1,2) pyridine (IMPY) under positive (+) mode. The gradient elution was set to 6 min, and the corresponding peak time of melatonin and its isotope melatonin-D4 was 3.14 min, while the peak time for the internal standard IMPY was 3.24 min. Next, we established and optimized the molecule receptor saturation binding assay based on LC-MS to determine the melatonin affinity for beta-amyloid (Abeta). Melatonin showed a high and specific binding for Abeta. The corresponding equilibrium dissociation constant (Kd) of melatonin with Abeta 1-40 and Abeta 1-42 was 814.37 AE 36.62 and 628.33 AE 13.57 nmolÁL À1 ; besides, the Kd of melatonin with mixed plaques (1-40 and 1-42) was 461.13 AE 45.37 nmolÁL À1 . The results may suggest the potential mechanism of action of MT on Abeta and provide a theoretical basis for the improvement of MT treatment of Alzheimer's disease.

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Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways

Cited by 665 publications

References 339 publications

Melatonin: A pleiotropic molecule regulating inflammation

Melatonin: A pleiotropic molecule regulating inflammation

The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling

Melatonin binds with high affinity and specificity to beta‐amyloid: LC‐MS provides insight into Alzheimer’s disease treatment

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