Melatonin Beyond Its Classical Functions

1-22 The perception of melatonin as a mediator of darkness, formed in a circadian fashion, circulating in subnanomolar concentrations, and removed as 6-sulfatoxymelatonin, reflects only a sector within a spectrum of actions. This ubiquitous compound present in bacteria and eucaryotes is exceptionally pleiotropic, in terms of binding proteins, receptor distribution, G protein coupling, electron-exchange reactions, and secondary effects by metabolites, such as 5- methoxytryptamine and methoxylated kynuramines. Membrane receptors are located, e.g., in the vertebrate suprachiasmatic nucleus, pars tuberalis, brain, vasculature, and leukocytes. Binding proteins include quinone reductase 2, ROR/RZR transcription factors, calmodulin, calreticulin, nuclear and mitochondrial proteins. Actions via hormonal subsystems, growth factors, neurotransmission and immune system lead to further secondary effects. Single-electron transfer reactions are basis of radical scavenging, non-enzymatic metabolism and interactions with electron transport systems. The metabolite, N1-acetyl-5-methoxykynuramine, is a potent inhibitor of prostaglandin synthesis and of neuronal NO synthase, an NO scavenger and a mitochondrial modulator.