Melatonin: signaling mechanisms of a pleiotropic agent.

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.