Melatonin formation in mammals: in vivo perspectives

Abstract

Melatonin is a hormone secreted from the pineal gland specifically at night and contributes to a wide array of physiological functions in mammals. Melatonin is one of the most well understood output of the circadian clock located in the suprachiasmatic nucleus. Melatonin synthesis is controlled distally via the circadian clock located in the suprachiasmatic nucleus and proximally regulated by norepinephrine released in response to the circadian clock signals. To understand melatonin synthesis in vivo, we have performed microdialysis analysis of the pineal gland, which monitors melatonin as well as the precursor (serotonin) and intermediate (N-acetylserotonin) of melatonin synthesis in freely moving animals in realtime at high resolution. Our data revealed a number of novel features of melatonin production undetected using conventional techniques, which include (1) large inter-individual variations of melatonin onset timing; (2) circadian regulation of serotonin synthesis and secretion in the pineal gland; and (3) a revised view on the rate-limiting step of melatonin formation in vivo. This article will summarize the main findings from our laboratory regarding melatonin formation in mammals.

Fig. 1

Secretion profiles of 5-HT, NAS and melatonin from pineal microdialysis of a rat. All three compounds display marked circadian rhythms in both light and dark (LD) and constant dark (DD) conditions with nocturnal increase in secretion

Fig. 2

Inter-individual and inter-species variation of melatonin onset timing. Three Degus (red dots), 5 Sprague Dawley rats (purple dots), and 7 Wistar rats (green dots) are shown. The onset timing is defined as when melatonin reaches 20% of daily maximum level, which is marked by the dashed line

Fig. 3

The total 5-HT output displays marked circadian rhythm with high levels at night. The total 5-HT is calculated as the sum of 5-HT, NAS (N-acetylated 5-HT), and melatonin (final metabolic product of 5-HT in the pineal)

Fig. 4

NAS is secreted in molar excess of melatonin in all outbred rats tested

Fig. 5

Amino acid sequence comparison of AANAT from degu and other mammalian species. The sequence comparison was performed using MacVector ClustalW alignment program and was color-coded based on functionality of the amino acids. Acidic residues were marked in red, basic residues in blue, hydrophobic residues in gray, and hydrophilic residues in purple. The numbers indicated on the upper right lines denote the amino acid positions based on the degu AANAT sequence