Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase messenger ribonucleic acid in the rat pineal gland (original) (raw)
Related papers
Journal of Neurochemistry, 2005
In mammals it has been thought that the circadian clock localizes only in the suprachiasmatic nucleus of the hypothalamus. Recent studies have revealed that certain brain regions and peripheral tissues may also have intrinsic circadian clocks. However, the roles played by 'peripheral circadian clocks' have not been fully elucidated. In this study, we investigated their function using mouse pineal glands, and found that expression of the arylalkylamine N-acetyltransferase (Aa-Nat, EC 2.3.1.87, the rate-limiting enzyme of melatonin synthesis) gene after adrenergic receptor stimulation depended on the time of day even in vitro (gating). Phase-dependent Aa-Nat responses were observed in both melatonin-proficient and melatonin-deficient mouse pineal glands. Phosphodiesterases are unlikely to suppress Aa-Nat induction because a phosphodiesterase inhibitor itself had no effect on the mRNA levels. Puromycin was ineffective in inducing Aa-Nat mRNA levels in either the presence or absence of isoproterenol, suggesting that newly synthesized proteins may not be necessary to gate the Aa-Nat responses. We also discovered circadian dependence of the expression of Period1-luminescence in Period1-luciferase transgenic mouse pineal glands: circadian clocks may be functional in culture. Aa-Nat mRNA levels showed no significant circadian rhythms in the absence of isoproterenol, thus suggesting that Aa-Nat mRNA levels are induced by adrenergic mechanisms, not by a pineal circadian clock. Our results suggest that the pineal circadian clock may determine timing when Aa-Nat gene expression can respond to inputs from the master circadian clock in the suprachiasmatic nucleus, e.g. adrenergic stimulation.
Ontogeny of a diurnal rhythm in arylalkylamine-N-acetyltransferase mRNA in rat pineal gland
Neuroscience Letters, 1998
Melatonin synthesis in the pineal gland of adult rats is linked to cAMP-dependent transcriptional and post-transcriptional regulatory mechanisms affecting its rate-limiting enzyme, the arylalkylamine-N-acetyltransferase (AA-NAT). During development of the pineal gland, neuronal control gains access to the earlier matured cAMP-signaling pathway to shape the day-night rhythm in AA-NAT enzymatic activity. By semiquantitative in situ hybridization we analyzed if the developmental onset of a rhythmic AA-NAT activity is correlated to a temporally parallel onset in AA-NAT transcription. We found that AA-NAT mRNA levels in rat pineal gland become rhythmic at postnatal day 5. Thus, AA-NAT gene transcription in rat pineal gland starts to show day-night differences shortly prior to the appearance of a rhythmic AA-NAT activity.
Journal of Biological Rhythms, 1999
In the pineal gland, synthesis of melatonin requires O-methylation catalyzed by hydroxyindole-O-methyltransferase (HIOMT; EC 2.1.1.4). We investigated in vivo the molecular mechanisms involved in the regulation of rat pineal HIOMT messenger RNA (mRNA) expression and activity using in situ hybridization and radioenzymatic assay. HIOMT mRNA levels and activity are both detectable during the daytime and display nocturnal increases of 100% and 30%, respectively. These variations are controlled by the endogenous clock, as they persist in constant darkness. The nocturnal increase in HIOMT mRNA mainly results from a  1 -adrenergic stimulation of HIOMT gene expression without requiring de novo synthesis of a transcription factor. In contrast, the nocturnal increase in HIOMT
Chick pineal clock regulates serotonin N -acetyltransferase mRNA rhythm in culture
Proceedings of the National Academy of Sciences, 1997
Melatonin production in the chick pineal gland is high at night and low during the day. This rhythm reflects circadian changes in the activity of serotonin N -acetyltransferase (arylalkylamine N -acetyltransferase, AA-NAT; EC 2.3.1.87 ), the penultimate enzyme in melatonin synthesis. In contrast to the external regulation of pineal rhythms in mammals by the suprachiasmatic nucleus, rhythmic changes in AA-NAT activity in cultured chick pineal cells are controlled by an oscillator located in the pineal cells themselves. Here we present evidence that the chick pineal clock generates a rhythm in the abundance of AA-NAT mRNA in cultured cells that parallels the rhythm in AA-NAT activity. In contrast, elevating cAMP by forskolin treatment markedly increases AA-NAT activity without producing strong changes in AA-NAT mRNA levels, and lowering cAMP by norepinephrine treatment decreases enzyme activity without markedly decreasing mRNA. These results suggest that clock-controlled changes in AA...
Journal of Neurochemistry, 2002
Abstract: The circadian rhythms in melatonin production in the chicken pineal gland and retina reflect changes in the activity of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase; AA-NAT; EC 2.3.1.87). Here we determined that the chicken AA-NAT mRNA is detectable in follicular pineal cells and retinal photoreceptors and that it exhibits a circadian rhythm, with peak levels at night. AA-NAT mRNA was not detected in other tissues. The AA-NAT mRNA rhythm in the pineal gland and retina persists in constant darkness (DD) and constant lighting (LL). The amplitude of the pineal mRNA rhythm is not decreased in LL. Light appears to influence the phase of the clock driving the rhythm in pineal AA-NAT mRNA in two ways: The peak is delayed by ∼6 h in LL, and it is advanced by >4 h by a 6-h light pulse late in subjective night in DD. Nocturnal AA-NAT mRNA levels do not change during a 20-min exposure to light, whereas this treatment dramatically decreases AA-NAT activity. These observations suggest that the rhythmic changes in chicken pineal AA-NAT activity reflect, at least in part, clock-generated changes in mRNA levels. In contrast, changes in mRNA content are not involved in the rapid light-induced decrease in AA-NAT activity.
Rhythmic transcription: the molecular basis of circadian melatonin synthesis
Trends in Neurosciences, 1997
Adaptation to a changing environment is an essential feature of physiological regulation. The day/night rhythm is translated into hormonal oscillations governing the physiology of all living organisms. In mammals the pineal gland is responsible for the synthesis of the hormone melatonin in response to signals originating from the endogenous clock located in the hypothalamic suprachiasmatic nucleus (SCN). The molecular mechanisms involved in rhythmic synthesis of melatonin involve the CREM gene, which encodes transcription factors responsive to activation of the CAMP signalling pathway. The CREM product, ICER, is rhythmically expressed and participates in a transcriptional autoregulatory loop which also controls the amplitude of oscillations of serotonin Nacetyl transferase (AANAT), the rate-limiting enzyme of melatonin synthesis. In contrast, chick pinealocytes possess an endogenous circadian pacemaker which directs AANAT rhythmic expression. CAMP-responsive activator transcription factors CRJZB and ATFl and the repressor ICER are highly conserved in the chick with the notable exception of ATFl that possesses two glutaminerich domains in contrast to the single domain encountered to date in mammalian systems. ICER is CAMP inducible and undergoes a characteristic day-night oscillation in expression reminiscent of AA-NAT, but with a peak towards the end of the night. Interestingly CREB appears to be phosphorylated constitutively with a transient fall occurring at the beginning of the night. Thus, a transcription factor modulates the oscillatory levels of a hormone. (0 Elsevier, Paris) AANAT / CREM / melatonin / pineal
Biochemical and Biophysical Research Communications, 1999
The hormone melatonin, secreted primarily from the pineal gland, plays an important physiological role in synchronizing biological rhythms and neuroendocrine. Presently, we find the expression of the serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT) mRNA, the rate-limiting enzyme in the conversion of serotonin to melatonin, in the rat suprachiasmatic nucleus (SCN) which contains the biological circadian clock in mammals. AA-NAT mRNA content in rat SCN did not show a significant circadian rhythm. However, AA-NAT enzyme activity was lowest at midday and highest at early night, and the rhythm persisted under constant dark conditions. These results indicate that the rat SCN is capable of synthesizing melatonin and suggest that melatonin synthesis in the SCN may be regulated by the circadian clock at the post transcriptional level.