Melatonin Signaling

Melatonin is a hormone secreted mainly by the pineal gland or epiphysis, and in small quantity by the retina. Dissemination of circadian information relies on the activation of melatonin receptors, which are most prominently expressed in the suprachiasmatic nucleus (SCN), and the hypophyseal pars tuberalis, but also in many other tissues. 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 its plasma membrane receptors, and/or in the nanomolar range to nuclear receptors (RZR/ROR), as well as to calmodulin. At higher concentrations, melatonin exhibits a free radical scavenging function. Two of the melatonin receptors are GPCRs (MTNR1A and MTNR1B), while the third belongs to the family of quinone reductases. MTNR1A and MTNR1B can couple to multiple signal transduction cascades, whereas the signaling cascades mediating the responses of the third receptor are yet to be elucidated.Plasma membrane melatonin receptors are expressed mainly in the CNS, whereas RZR/ROR is prominently expressed both in the periphery and the brain. The action of plasma membrane receptors have been associated with circadian rhythmicity, whereas direct effects of melatonin in the periphery, such as immunomodulation, cellular growth, bone differentiation, and circadian rhythmicity mainly appear to be mediated by RZR. After binding to its plasma membrane receptors, melatonin changes the conformation of the α-subunit of specific intracellular G proteins. It regulates cell function via second messengers such as cAMP, Ca2+, cGMP, DAG, and arachidonic acid. Besides the cAMP-dependent cascade, MTNR1A can couple to a PLC-dependent signal transduction cascade directly or indirectly via G-βγ subunits for phosphoinositide turnover, and can also activate PKC signaling. On the other hand, activation of MTNR1A promotes ERK/MAPK signaling. These receptors can also modulate the formation of arachidonic acid and activation of JNK. 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 a decrease in cAMP and in phosphorylation of the potassium channels by PKA. Melatonins can also induce vasoconstriction in cerebral arteries through inhibition of potassium channels. MTNR1As also couple to the GIRK/Kir3 channels.Similar to MTNR1A, activation of the MTNR1B by melatonin inhibits cAMP formation. Additionally, MTNR1B activation leads to the inhibition of cGMP formation through proteins upstream of guanylate cyclase such as NOS. In the SCN, melatonin increases PKC activity through activation of Gαq, which stimulates the PLC signaling cascade. Other responses of melatonin receptors include phase advance of circadian rhythms in the isolated SCN, enhancement of cell-mediated and humoral immunity, inhibition of leukocyte rolling in the microvasculature, and inhibition of proliferation of human choriocarcinoma cells, most likely by delay of G1 to S phase transition. Furthermore, activation of MTNR1B decreases the expression of the glucose transporter GLUT4, which in turn decreases glucose uptake in human brown adipocytes.Melatonin binds to calmodulin with high affinity and acts as an antagonist of calmodulin-mediated CalmKII activation. 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. Melatonin has been proclaimed to be a cure-all for a wide variety of conditions,ranging from insomnia to cancer, to acting as an anti-aging agent.