Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism.
Conversion of serotonin to N-acetylserotonin, the precursor of the circadian neurohormone melatonin, is catalyzed by serotonin N-acetyltransferase (AANAT) in a reaction requiring acetyl coenzyme A (AcCoA). AANAT is a globular protein consisting of an eight-stranded beta sheet flanked by five alpha helices; a conserved motif in the center of the beta sheet forms the cofactor binding site. Three polypeptide loops converge above the AcCoA binding site, creating a hydrophobic funnel leading toward the cofactor and serotonin binding sites in the protein interior. Two conserved histidines not found in other NATs are located at the bottom of the funnel in the active site, suggesting a catalytic mechanism for acetylation involving imidazole groups acting as general acid/base catalysts. (+info)
Prolactin replacement fails to inhibit reactivation of gonadotropin secretion in rams treated with melatonin under long days.
This study tested the hypothesis that prolactin (PRL) inhibits gonadotropin secretion in rams maintained under long days and that treatment with melatonin (s.c. continuous-release implant; MEL-IMP) reactivates the reproductive axis by suppressing PRL secretion. Adult Soay rams were maintained under long days (16L:8D) and received 1) no further treatment (control, C); 2) MEL-IMP for 16 wk and injections of saline/vehicle for the first 8 wk (M); 3) MEL-IMP for 16 wk and exogenous PRL (s.c. 5 mg ovine PRL 3x daily) for the first 8 wk (M+P). The treatment with melatonin induced a rapid increase in the blood concentrations of FSH and testosterone, rapid growth of the testes, an increase in the frequency of LH pulses, and a decrease in the LH response to N-methyl-D,L-aspartic acid. The concomitant treatment with exogenous PRL had no effect on these reproductive responses but caused a significant delay in the timing of the sexual skin color and growth of the winter pelage. These results do not support the hypothesis and suggest that PRL at physiological long-day concentrations, while being totally ineffective as an inhibitor of gonadotropin secretion, acts in the peripheral tissues and skin to maintain summer characteristics. (+info)
Melatonin inhibits release of luteinizing hormone (LH) via decrease of [Ca2+]i and cyclic AMP.
The role of [Ca2+]i and cAMP in transduction of the melatonin inhibitory effect on GnRH-induced LH release from neonatal rat gonadotrophs has been studied, because melatonin inhibits the increase of both intracellular messengers. Treatments increasing Ca2+ influx (S(-) Bay K8644 or KCI) or cAMP concentration (8-bromo-cAMP or 3-isobutyl-1-methylxanthine) potentiated the GnRH-induced LH release and partially diminished the inhibitory effect of melatonin. Combination of the treatments increasing cAMP and calcium concentrations blocked completely the melatonin inhibition of LH release. The combined treatment with 8-bromo-cAMP and S(-) Bay K8644 also blocked the melatonin inhibition of GnRH-induced [Ca2+]i increase in 89 % of the gonadotrophs, while any of the treatments alone blocked the melatonin effect in about 25 % of these cells. These observations suggest that a cAMP-dependent pathway is involved in regulation of Ca2+ influx by melatonin and melatonin inhibition of LH release may be mediated by the decrease of both messengers. (+info)
Two arylalkylamine N-acetyltransferase genes mediate melatonin synthesis in fish.
Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT, EC 22.214.171.124) is the first enzyme in the conversion of serotonin to melatonin. Large changes in AANAT activity play an important role in the daily rhythms in melatonin production. Although a single AANAT gene has been found in mammals and the chicken, we have now identified two AANAT genes in fish. These genes are designated AANAT-1 and AANAT-2; all known AANATs belong to the AANAT-1 subfamily. Pike AANAT-1 is nearly exclusively expressed in the retina and AANAT-2 in the pineal gland. The abundance of each mRNA changes on a circadian basis, with retinal AANAT-1 mRNA peaking in late afternoon and pineal AANAT-2 mRNA peaking 6 h later. The pike AANAT-1 and AANAT-2 enzymes (66% identical amino acids) exhibit marked differences in their affinity for serotonin, relative affinity for indoleethylamines versus phenylethylamines and temperature-activity relationships. Two AANAT genes also exist in another fish, the trout. The evolution of two AANATs may represent a strategy to optimally meet tissue-related requirements for synthesis of melatonin: pineal melatonin serves an endocrine role and retinal melatonin plays a paracrine role. (+info)
Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms.
1. The circadian timing system has been implicated in age-related changes in sleep structure, timing and consolidation in humans. 2. We investigated the circadian regulation of sleep in 13 older men and women and 11 young men by forced desynchrony of polysomnographically recorded sleep episodes (total, 482; 9 h 20 min each) and the circadian rhythms of plasma melatonin and core body temperature. 3. Stage 4 sleep was reduced in older people. Overall levels of rapid eye movement (REM) sleep were not significantly affected by age. The latencies to REM sleep were shorter in older people when sleep coincided with the melatonin rhythm. REM sleep was increased in the first quarter of the sleep episode and the increase of REM sleep in the course of sleep was diminished in older people. 4. Sleep propensity co-varied with the circadian rhythms of body temperature and plasma melatonin in both age groups. Sleep latencies were longest just before the onset of melatonin secretion and short sleep latencies were observed close to the temperature nadir. In older people sleep latencies were longer close to the crest of the melatonin rhythm. 5. In older people sleep duration was reduced at all circadian phases and sleep consolidation deteriorated more rapidly during the course of sleep, especially when the second half of the sleep episode occurred after the crest of the melatonin rhythm. 6. The data demonstrate age-related decrements in sleep consolidation and increased susceptibility to circadian phase misalignment in older people. These changes, and the associated internal phase advance of the propensity to awaken from sleep, appear to be related to the interaction between a reduction in the homeostatic drive for sleep and a reduced strength of the circadian signal promoting sleep in the early morning. (+info)
Potentiation of isoniazid activity against Mycobacterium tuberculosis by melatonin.
The limited number of effective antituberculosis drugs available necessitates optimizing current treatments. We show that melatonin, which is synthesized in the pineal gland, can cause at least a threefold increase in the efficacy of isoniazid. This suggests that tuberculosis chemotherapy can be improved by innate molecules such as melatonin. (+info)
The relationship between 6-sulphatoxymelatonin and polysomnographic sleep in good sleeping controls and wake maintenance insomniacs, aged 55-80 years.
The pineal hormone, melatonin, is reported to possess hypnotic properties. This has led to an investigation of the relationship between the endogenous melatonin rhythm and sleep. However, this relationship has yet to be fully examined in aged insomniacs and controls. From media advertisements, 16 good sleeping controls (11F, 5M) and 16 sleep maintenance insomniacs (11F, 5M), aged over 55 years, were recruited to participate in a study involving four nights of polysomnographically (PSG) measured sleep followed by a 26 h constant routine. During the constant routine, 2 h urine samples were collected and analysed for the melatonin metabolite, 6-sulphatoxymelatonin (aMT.6S). This was used to determine total melatonin excretion. As well, the following circadian melatonin parameters were calculated from fifth order polynomial curve fitting analyses, the goodness of the polynomial curve fit, peak melatonin concentration, the phase of the melatonin rhythm, and melatonin and sleep rhythm synchrony. Apart for one control, all subjects showed significant circadian melatonin rhythms. Although insomniacs showed a greater amount of wakefulness, less sleep in total, and lower sleep efficiency, no significant group differences were observed in any of the melatonin parameters. In addition, while subjects with more reliable melatonin curve fits showed shorter sleep latencies and higher sleep efficiencies, correlational analyses revealed no other significant relationships between any melatonin and PSG sleep parameters. Overall, the present results suggest that neither melatonin amplitude nor phase are related to sleep quality in the aged. (+info)
A 50-Hz electromagnetic field impairs sleep.
In view of reports of health problems induced by low frequency (50-60 Hz) electromagnetic fields (EMF), we carried out a study in 18 healthy subjects, comparing sleep with and without exposure to a 50 Hz/1 mu Tesla electrical field. We found that the EMF condition was associated with reduced: total sleep time (TST), sleep efficiency, stages 3 + 4 slow wave sleep (SWS), and slow wave activity (SWA). Circulating melatonin, growth hormone, prolactin, testosterone or cortisol were not affected. The results suggest that commonly occurring low frequency electromagnetic fields may interfere with sleep. (+info)