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 Melatonin Signaling

Melatonin (5-methoxy-N-acetyltryptamine) is a hormone synthesized in the retina, pineal and Harderian gland. The primary source of plasma (circulating platelet-associated) melatonin is the pineal gland. Melatonin synthesis is induced by the absence of light. It is synthesized from serotonin in two enzymatic steps, N-acetylation and O-methylation. Acetylation and methylation are catalyzed by arylalkylamine N-acetyltransferase (NAT; EC 2.3.1.87) and methylation hydroxyindole-O-methyltransferase (EC 2.1.1.4), respectively. Melatonin is a transmitter of photoperiodic information. It is a regulator of the maturation and differentiation of neurons; circadian rhythmicity; nitric oxide metabolism; and the hypothalamic-pituitary-gonadal axis (reproductive cycle). Melatonin functions as an antioxidant that protects cells from mitochondrial apoptosis induced by oxidative stress. Melatonin is an inhibitor of lipid peroxidation.

Melatonin affects cell processes at several levels, depending upon cell type and context melatonin can mediate its affects through high affinity cell membrane receptors and/or nuclear receptors. Melatonin binds to two specific G-protein coupled receptors (GPCR), MT1 (MTNR1A/MEL1A) and MT2 (MTNR1B/MEL1B). One or both of these receptors exists on a variety of cell types, but they are found in abundance in the pituitary par tuberalis (PT); the hypothalamus suprachiasmatic nuclei (SCN); the cerebral and cerebellar cortex and the retina. MT1/2 GPCR receptors are associated primarily with G-protein Galphai (Gαi), Galphao (Gαo), and Galphaq (Gαq), subunits. Signaling via these receptors is differentially regulated and tissue-specific. Melatonin GPCR signaling is generally a negative regulator of cell function via reduction of intracellular second messengers such as cAMP, Ca2+, and cGMP via Gαi/o subunits. The MTNR1/2 receptors activate G-protein alphaq (Gαq) subunits that stimulate phospholipase C, leading to DAG and IP3 actions. Melatonin regulates cell processes via nuclear signaling via transcription factors, RZR/ROR (RZR alpha and beta). Genes regulated by RZR/ROR include 5-lipoxygenase, p21WAF1/C1P1, apolipoprotein A-1, N-myc and Purkinje cell protein 2.