Modulation of Aanat gene transcription in the rat pineal gland

Abstract

The main function of the rat pineal gland is to transform the circadian rhythm generated in the suprachiasmatic nucleus into a rhythmic signal of circulating melatonin characterized by a large nocturnal increase that closely reflects the duration of night period. This is achieved through the tight coupling between environmental lighting and the expression of arylalkylamine-Nacetyltransferase, the rhythm-controlling enzyme in melatonin synthesis. The initiation of Aanat transcription at night is controlled largely by the norepinephrine-stimulated phosphorylation of cAMP response element-binding protein by protein kinase A. However, to accurately reflect the duration of darkness, additional signaling mechanisms also participate to fine-tune the temporal profile of adrenergic-induced Aanat transcription. Here, we reviewed some of these signaling mechanisms, with emphasis on the more recent findings. These signaling mechanisms can be divided into two groups: those involving modification of constitutively expressed proteins and those requiring synthesis of new proteins. This review highlights the pineal gland as an excellent model system for studying neurotransmitter-regulated rhythmic gene expression. Keywords: arylalkylamine-N-acetyltransferase, aurora kinase, cyclic AMP response element-binding protein, histone, pineal, salt-inducible kinase. nucleus which sends a stimulatory signal to the pineal gland at night by way of a neural circuit that includes both central and peripheral neuronal structures (Moore and Klein 1974). The circadian clock in the suprachiasmatic nucleus itself is synchronized to environmental lighting via neural signal transmitted through the retinal hypothalamic tract (Klein et al. 1991;Ganguly et al. 2002). Such arrangement ensures that the stimulation of the pineal gland is tightly coupled to the environmental light/dark cycle. Within the pinealocyte, the biosynthesis of melatonin involves N-acetylation of serotonin by arylalkylamine-Nacetyltransferase (AA-NAT), followed by methylation of the 5-hydroxyl group by hydoxyindole-O-methyltransferase, with the former functioning as a rate-limiting gating mechanism in this biosynthetic pathway (Klein 1985). Hence the day/night difference in the production of melatonin is in fact a reflection of the circadian variation in the activity of AA-NAT in the pineal gland . Considering the importance of melatonin in different aspects of neurobiology (Arendt 1995), the control mechanism that regulates AA-NAT activity has attracted the attention of researchers in circadian biology.In the rat pineal gland, the increase in the level of AA-NAT activity at night is mainly because of increased synthesis of AA-NAT protein. The signal transduction pathway that regulates this process has been expertly reviewed Ganguly et al. 2002;Maronde and Stehle 2007). In brief, the nightly release of NE from the sympathetic nerve stimulates both a-and b-adrenergic receptors, resulting in a 100-fold increase in the level of cAMP (Klein 1985). This in turn causes an increase...

Circadian rhythms and sleep—the metabolic connection

“…This results in elevation of adenosine monophosphate (5′-AMP) and increases the synthesis of the rate-limiting enzyme of melatonin synthesis, the arylalkylamine-N-acetyltransferase (Aanat) (reviewed in [32]). There is evidence that the synthesis of Aanat mRNA is regulated by the circadian clock by translational mechanisms [38].…”

Chronobiology and obesity: the orchestra out of tune

“…Thus, for example, melatonin future science group Chronobiology & obesity | PersPective peaks during the night in response to nocturnal activation by SCN of the limiting enzyme AANAT (arylalkylamine N-acetyltransferase) in the pineal gland [15]. Cortisol peak should occur in the morning in response to suprarenal activation by ACTH (adrenocorticotropic hormone), which in turn, is under SCN control [1,16].…”

MicroRNAs in the Pineal Gland

“…Genes that are relevant to pineal biology and have predicted binding sites for multiple pineal gland-enriched miRNAs include Snf1lk, Per2, and Mat2a. Snf1lk may regulate the timing of the peak of Aanat expression (49) and has predicted binding sites for miR-182 and miR-96. Per2 has recently been reported to have an endogenous circadian rhythm in pineal cells (50) and may be targeted by miR-24 and miR-30.…”