Melatonin: Signaling mechanisms of a pleiotropic agent

Abstract

Melatonin acts both as a hormone of the pineal gland and as a local regulator molecule in various tissues. Quantities of total tissue melatonin exceed those released from the pineal. With regard to this dual role, to the orchestrating, systemic action on various target tissues, melatonin is highly pleiotropic. Numerous secondary effects result from the control of the circadian pacemaker and, in seasonal breeders, of the hypothalamic/pituitary hormonal axes. In mammals, various binding sites for melatonin have been identified, the membrane receptors MT(1) and MT(2), which are of utmost chronobiological importance, ROR and RZR isoforms as nuclear receptors from the retinoic acid receptor superfamily, quinone reductase 2, calmodulin, calreticulin, and mitochondrial binding sites. The G protein-coupled receptors (GPCRs) MT(1) and MT(2) are capable of parallel or alternate signaling via different Galpha subforms, in particular, Galpha(i) (2/) (3) and Galpha(q), and via Gbetagamma, as well. Multiple signaling can lead to the activation of different cascades and/or ion channels. Melatonin frequently decreases cAMP, but also activates phospholipase C and protein kinase C, acts via the MAP kinase and PI3 kinase/Akt pathways, modulates large conductance Ca(2+)-activated K(+) and voltage-gated Ca(2+) channels. MT(1) and MT(2) can form homo and heterodimers, and MT(1) interacts with other proteins in the plasma membrane, such as an orphan GPCR, GPR50, and the PDZ domain scaffolding protein MUPP1, effects which negatively or positively influence signaling capacity. Cross-talks between different signaling pathways, including influences of the membrane receptors on nuclear binding sites, are discussed. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

Melatonin: A pleiotropic molecule regulating inflammation

“…Even though the mechanisms through which melatonin stimulates these signal transduction pathways have been extensively studied [12][13][14][15][16][17][18][19][20][21], little is known about the resulting cellular effects: MT1/MT2 receptors have been shown to mediate melatonin-dependent decrease of tumor cell proliferation [22] and anti-apoptotic effects [23][24][25]; MT1 seems to be responsible for the general response to photoperiodic signals [26].…”

Alleviating effects of melatonin on oxidative changes in the testes and pituitary glands evoked by subacute chlorpyrifos administration in Wistar rats

“…This cascade reaction makes melatonin a highly effective antioxidant, even at low concentrations, in protecting cells from oxidative stress [27] . Melatonin diminishes the destruction of DNA, proteins and lipids that occur as a result of their reactions with ROS and RNS [28] as it easily crosses the cell membranes and the blood-brain barrier [29] . Since antigonadal action of OPs may involve the pituitary gland and testes couple with the established role of oxidative stress in the etiopathogenesis of OP-evoked toxicity, the present study was therefore aimed at evaluating the alleviating effect of melatonin on subacute CPF-induced oxidative stress in both organs in Wistar rats.…”

Efeito da melatonina sobre a viabilidade de células granulares de cerebelo em cultura depende do contexto celular

“…Por outro lado, por ser uma molécula anfipática a melatonina é capaz de atravessar a membrana plasmática e interagir com moléculas citosólicas e nucleares com uma afinidade muito menor do que para os receptores de membrana. (Shida et al, 1994;Hardeland, 2009;Luchetti et al, 2010).…”

“…(originalmente descritos como Mel1a e Mel1b, respectivamente) são expressos tanto individualmente como em conjunto em vários tecidos e órgãos (Hardeland, 2009). O subtipo MT1 é amplamente expresso no SNC, em órgãos reprodutores, rim, fígado, vasos e pele.…”

“…Além da QR2 a melatonina interage com outras moléculas citosólicas como, por exemplo, a calmodulina (CaM) que forma um complexo com cálcio (Hardeland, 2009;Luchetti et al, 2010). Essa interação leva a inibição da atividade de proteínas quinases, como a CaM quinase II (CaMKII) (Benítez-King et al, 1996) e da isoforma constitutiva da sintase de óxido nítrico (cNOS) (León et al, 2000).…”