Melatonin Signaling
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Melatonin Signaling

In mammals, the circadian system is comprised of three major components: the lateral eyes, the hypothalamic SCN (Suprachiasmatic Nucleus) and the pineal gland. The SCN harbours the endogenous oscillator that is entrained everyday to the ambient lighting conditions via retinal input. Among the many circadian rhythms in the body that are driven by SCN output, the synthesis of Melatonin (N-Acetyl-5 Methoxy-Tryptamine) in the pineal gland functions as a hormonal message encoding for the duration of darkness. Melatonin  is a hormone secreted mainly by the pineal gland or epiphysis; it is also produced, but in much smaller quantities, by the retina. Melatonin is produced nocturnally, and is a neurochemical representation of time. Dissemination of this circadian information relies on the activation of Melatonin receptors, which are most prominently expressed in the SCN, and the hypophyseal pars tuberalis, but also in many other tissues (Ref.1).

Melatonin can activate or inhibit signal transduction cascades through receptors or independent of receptors. The hormone binds with high affinity in the picomolar range to the membrane receptors, and/or in the nanomolar range to the nuclear receptors (RZR/ROR) as well as to Calmodulin. At even higher concentrations Melatonin has a free radical scavenging function. (Ref.2). There are multiple receptor subtypes available to which Melatonin can bind and activate. Two of the membrane Melatonin receptors subtypes are GPCRs (G-Protein Coupled Receptors) while the third, which was recently affinity-purified, belongs to the family of quinone reductases (Ref.3). Each of the G-protein coupled Melatonin receptor subtypes, denoted as: MTNR1A (Melatonin Receptor-1A) and MTNR1B(Melatonin Receptor-1B), can couple to multiple signal transduction cascades whereas the signal transduction cascades mediating the responses of the third receptor are still to be elucidated. Membrane Melatonin receptors are expressed mainly in the central nervous system, whereas RZR (Retinoid Z Receptors)/ROR (Retinoid Orphan Receptors) is prominently expressed both in the periphery and the brain (Ref.4). This would allow three cases for Melatonin signaling through nuclear and membrane receptors to be distinguished: cells that express (1) membrane Melatonin receptors and RZR in parallel, (2) only membrane melatonin receptors, or (3) only RZR. Inasmuch as RZR is rather ubiquitously expressed, the first case may apply to various structures of the central nervous system (SCN, retina, pars tuberalis, and the pineal gland. The action of membrane Melatonin receptors and their specific agonists have been associated with circadian rhythmicity, whereas direct effects of melatonin in the periphery, such as immunomodulation, cellular growth, and bone differentiation, including circadian rhythmicity mainly appear to be mediated by RZR (Ref.2).

After binding to its membrane-bound receptors, melatonin changes the conformation of the Alpha-subunit of specific intracellular G proteins. It  regulates cell function via intracellular second messengers such as cAMP (Cyclic Adenosine Monophosphate), Ca2+, cGMP (Cyclic Guanosine Monophosphate), DAG (Diacylglycerol), PKC (Protein Kinase-C), and Arachidonic acid; however, the signaling pathways activated by melatonin appear to be differentially regulated and tissue-specific (Ref.5). Melatonin, through activation of MTNR1A and subsequently, G-AlphaI inhibits cAMP formation, PKA (Protein Kinase-A) activity, which then results in the decrease in CREB (cAMP-Responsive Element Binding Protein) phosphorylation. However, in some cells, MTNR1As have also been shown to stimulate cAMP probably through G-AlphaS. Besides the cAMP-dependent cascade, MTNR1A can couple to a stimulation of PLC-dependent signal transduction cascades directly or indirectly via G-BetaGamma subunits for phosphoinositide turnover and can also activate PKC. On the other hand, activation of the MTNR1A increases phosphorylation of MAPK (Mitogen-Activated Protein Kinase) or MEK1 (MAPK/ERK Kinase-1) and MEK2 (MAPK/ERK Kinase-2) and ERK1/2 (Extracellular Signal-Regulated Kinases 1 and 2). These receptors can also modulate the formation of arachidonic acid and JNKs (c-Jun N-terminal Kinase). Activator protein-1, a transcription factor formed by the immediate-early gene products c-Fos and c-Jun, has been shown to be extensively regulated through the MAPK pathway, specifically ERK1, ERK2 and JNKs (Ref.6). In addition, several functional responses to Melatonin are mediated by regulation of ion channels. Activation of MTNR1As potentiates vasoconstriction by blocking calcium-activated potassium channels in smooth muscle. This blockade may result from decreases in cAMP and in phosphorylation of the calcium-activated potassium channels channel by PKA. Melatonin also directly vasoconstricts cerebral arteries through inhibition of calcium-activated potassium channels. MTNR1As also couple to the GIRK (G-protein-activated Inward Rectifier Potassium)/Kir 3 channels (Ref.4).

Levels of both cAMP and cGMP are modulated through activation of MTNR1Bs. Similar to the MTNR1A, activation of the MTNR1B by Melatonin inhibits cAMP formation. Additionally, MTNR1B activation leads to the inhibition of cGMP formation, through proteins upstream of the GC (Guanylyl Cyclase) such as NOS (Nitric Oxide Synthase) (Ref.2). In the SCN, Melatonin increases PKC activity through activation of GN-AlphaQ, which stimulates the PLC (Phospholipase-C) and DAG pathway. The Melatonin receptors also serves as the mediators of several other physiological responses to Melatonin These responses include (i) phase advance of circadian rhythms in the isolated SCN, which involves PKC activation; (ii) enhancement of cell-mediated and humoral immunity; (iii) inhibition of leukocyte rolling in the microvasculature; and (iv) inhibition of proliferation of human choriocarcinoma cells, probably by delay of the G1 to S cell cycle transition. Furthermore, activation of MTNR1B decreases the expression of the glucose transporter GLUT4 (Glucose Transporter-4) that in turn decreases glucose uptake in human brown adipocytes, modulates neuronal activity in the hippocampus, and mediates vasodilation in arterial beds (Ref.4).
The ability of melatonin to act independently from its receptors is attributed to its small and highly lipophilic nature and/or due to an active uptake mechanism. Melatonin binds to Calmodulin with high affinity and has been shown to act as a calmodulin antagonist. Melatonin inhibits CalmKII (Ca2+/Calmodulin Dependent Protein Kinase-II) activity, an abundant enzyme in the nervous system. In the brain it phosphorylates a broad spectrum of substrates, thus modulating important neuronal functions and cellular functions may be rhythmically regulated by melatonin modulation of calmodulin dependent protein phosphorylation. Melatonin scavenges oxygen-centered free radicals, especially the highly toxic hydroxyl radical, and neutralizes them by a single electron transfer, which results in detoxified radicals. The hormone may therefore protect macromolecules, particularly DNA, from oxidative damage (Ref.3). The subfamily of RZR or ROR includes the products of three genes: splicing variants of ROR-Alpha (ROR-Alpha1, ROR-Alpha2, ROR-Alpha3) which differ in the N-terminal domain, and RZR-Beta, and ROR-Gamma. The structure includes an N-terminal variable domain A/B with a constitutive AF1 (Activation Function-1), conservative DNA binding domain C, variable hinge domain D, relatively conservative ligand binding domain E containing a ligand-dependent AF2 (Activation Function-2), and an optional short domain F (Ref.5). Specific binding sites have been identified in promoter regions of a variety of genes, such as 5-LO (5-lipoxygenase), p21WAF1/CIP1, and BSP (Bone Sialoprotein). The subfamily members bind to DNA as monomers and recognize hormone response elements: ROREs/RZREs represented by 5-terminal extended half sites with the A/GGGTCA motif. The transcription factor RZR appears to mediate a direct gene regulatory action of the hormone. Besides circadian rhythm control in mammals, melatonin also plays an important role in the regulation of reproduction as well. This role is accomplished  by Melatonin through negative regulation of the signaling induced by GnRH (Gonadotropin-Releasing Hormone) in the gonadotrophs. Melatonin inhibits GnRH -induced increases in cAMP, DAG (Diacylglycerol), Ca2+ (Calcium), and c-Fos probably through the inhibition of cGMP (Cyclic Guanosine Monophosphate) in the neonatal gonadotrophs (Ref.7).

The pineal gland hormone has proved to suppress tumor growth in a number of experimental models, including undifferentiated neoplasms, sarcomas, and carcinomas (Ref.2). In light of its multiple functions, melatonin has been proclaimed to be a cure-all for everything from treating insomnia and cancer to acting as an anti-aging agent. In regard to melatonin actions as an anti-aging agent, it is known that secretion of the hormone is decreased during the aging process, and when administered to aging animals, it is capable of increasing their life span by almost 20% (Ref.4). Melatonin mechanisms are also related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, NOS activity and dopamine release inhibition, membrane stabilisation. The treatment of headache disorders with Melatonin and other chronobiotic agents is promising and there is a great potential for their use in headache treatment (Ref.8).