Analysis of Adrenergic Regulation of Melatonin Synthesis in Siberian Hamster Pineal Emphasizes the Role of HIOMT

Abstract

Seasonal variations of environmental factors are translated into annual fluctuations in synthesis and release of melatonin, which in turn acts as a neuroendocrine messenger for the synchronization of annual functions. So far, most studies performed to understand the regulation of melatonin synthesis have used the non seasonal laboratory rat. It was demonstrated that nocturnal melatonin synthesis depends on α- and β-adrenergic activation of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). In this study, we investigated the mechanisms of melatonin synthesis in the Siberian hamster, a seasonal species with marked photoperiodic variation in melatonin peak duration and amplitude. A β-adrenergic receptor agonist alone markedly stimulated AA-NAT activity and melatonin synthesis and release. An α-adrenergic receptor agonist, while having no effect per se, potentiated the β-adrenergic stimulation of AA-NAT activity both in vitro and in vivo. Strikingly, the potentiation of AA-NAT activity did not result in a potentiation of melatonin synthesis, suggesting that the rate of melatonin production is limited downstream in the metabolic pathway, most probably at the level of hydroxyindole-O-methyltransferase (HIOMT). HIOMT presented a constitutively high activity that was not acutely (within hours) stimulated by β-adrenergic agonist, but was rather up-regulated by chronic application of the agonist. This long-term β-adrenergic regulation may explain the reported large photoperiodic variation of HIOMT activity that drives the photoperiodic variation in melatonin peak.

Melatonin and the ovary: physiological and pathophysiological implications

“…Although NAT was thought to be the ratelimiting enzyme in melatonin biosynthesis, recent findings have shifted the emphasis to HIOMT as possibly being responsible for the circadian melatonin cycle. This idea developed when it was shown that elevated NAT activity, stimulated by an adrenergic-a and adrenergic-b receptor agonist, failed to promote melatonin production, whereas the increased activity of HIOMT was positively correlated with pineal melatonin production (18).…”

Night/Day Changes in Pineal Expression of >600 Genes

“…This has not been reported previously. Studies with rodents have revealed that expression of this enzyme can be regulated by adrenergic mechanisms (82,83). Other studies of this gene in Y79 cells, a human retinoblastoma-derived line, indicate that expression of the gene is controlled by 9-cis-retinoic acid (84).…”

Melatonin as an Endogenous Plant Regulatory Signal: Debates and Perspectives

“…The reaction step converting 5-hydroxytryptamine to Nacetylserotonin catalyzed by serotonin-N-acetyltransferase (AANAT) has long been thought of as the rate-limiting step (Boutin et al 2005). However, new evidence indicates that the next step in which N-acetylserotonin is converted to melatonin catalyzed by hydroxyindole-O-methyltransferase (HIOMT) may be the rate-limiting step (Ribelayga et al 2000;Ceinos et al 2004;Johnston et al 2004;Liu and Borjigin 2005).…”