Participation of Ca2+-Calmodulin-Dependent Protein Kinase II in the Antidepressant-Like Effects of Melatonin.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine secreted by the pineal gland during the dark phase of the photoperiod. Its main function is the synchronization of different body rhythms with the dark-light cycle. Research on melatonin has significantly advanced since its discovery and we now know that it has considerable significance in various physiological processes, including immunity, aging, and reproduction. Moreover, in recent years evidence of the pharmacological possibilities of melatonin has increased. Indoleamine, on the other hand, has antidepressant-like effects in rodents, which may be mediated by the activation of calcium-calmodulin-dependent kinase II (CaMKII) and are also related to the regulation of neuroplasticity processes, including neurogenesis, synaptic maintenance, and long-term potentiation. Remarkably, patients with major depression show decreased levels of circulating melatonin in plasma. This review presents evidence of the antidepressant-like effects of melatonin in preclinical models and the participation of CaMKII in these actions. CaMKII's role in cognition and memory processes, which are altered in depressive states, are part of the review, and the effects of melatonin in these processes are also reviewed. Furthermore, participation of CaMKII on structural and synaptic plasticity and the effects of melatonin are also described. Finally, the advantages of using melatonin in combination with other antidepressants such as ketamine for neuroplasticity are described. Evidence supports that CaMKII is activated by melatonin and downstream melatonin receptors and may be the common effector in the synergistic effects of melatonin with other antidepressants. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin causes antidepressant-like effects in mice through calmodulin kinase II stimulation of downstream melatonin receptors as well as the participation of this enzyme in neuroplasticity, memory, and cognition. Finally, we describe evidence about the effectiveness of antidepressant-like effects of melatonin in combination with ketamine.

Interaction of the Melatonin/Ca2+-CaM Complex with Calmodulin Kinase II: Physiological Importance.

Melatonin N-acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biologic activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation, where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to different proteins such as calmodulin: a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence supporting that melatonin binds to calmodulin in presence of calcium, and we discuss the effects of this indolamine on the activity of calmodulin kinase II as an inhibitor and as stimulator of calmodulin-dependent protein kinase II activity. We also provide a literature review supporting the relevance of melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient, conserved mechanism. Finally, we highlight the importance of antioxidant effects of melatonin on calmodulin preservation. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of calmodulin kinase II, the possible mechanisms involved, and the relevance on regulation of circadian rhythms and neurodevelopment. Finally, we describe evidence supporting that the binding of melatonin to calmodulin hydrophobic pockets may prevent the oxidation of methionine species with a shielding effect that preserves the functionality of calmodulin.

Melatonin: A Neurotrophic Factor?

Melatonin, N-acetyl-5-hydroxytryptamine, is a hormone that synchronizes the internal environment with the photoperiod. It is synthesized in the pineal gland and greatly depends on the endogenous circadian clock located in the suprachiasmatic nucleus and the retina's exposure to different light intensities. Among its most studied functions are the regulation of the waking-sleep rhythm and body temperature. Furthermore, melatonin has pleiotropic actions, which affect, for instance, the modulation of the immune and the cardiovascular systems, as well as the neuroprotection achieved by scavenging free radicals. Recent research has supported that melatonin contributes to neuronal survival, proliferation, and differentiation, such as dendritogenesis and axogenesis, and its processes are similar to those caused by Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5. Furthermore, this indolamine has apoptotic and anti-inflammatory actions in specific brain regions akin to those exerted by neurotrophic factors. This review presents evidence suggesting melatonin's role as a neurotrophic factor, describes the signaling pathways involved in these processes, and, lastly, highlights the therapeutic implications involved.