Pineal melatonin synthesis is altered in Period1 deficient mice.
Melatonin is an important endocrine signal for darkness in mammals. Transcriptional activation of the arylalkylamine-N-acetyltransferase gene encoding for the penultimate enzyme in melatonin synthesis drives the daily rhythm of the hormone in the pineal gland of rodents. Rhythmic arylalkylamine-N-acetyltransferase expression is controlled by the cAMP-signal transduction pathway and involves the activation of β-adrenergic receptors and the inducible cAMP early repressor. In addition, the rat arylalkylamine-N-acetyltransferase promoter contains an E-box element which can interact with clock proteins. Moreover, the pineal gland of mice shows a circadian rhythm in clock proteins such as the transcriptional repressor Period1, which has been shown to control rhythmic gene expression in a variety of tissues. However, the role of Period1 in the regulation of pineal melatonin synthesis is still unknown. Therefore, circadian rhythms in arylalkylamine-N-acetyltransferase, β-adrenergic receptor, and inducible cAMP early repressor mRNA levels (real time PCR), arylalkylamine-N-acetyltransferase enzyme activity (radiometric assay) and melatonin concentration radio immuno assay (RIA) were analyzed in the pineal gland of mice with a targeted deletion of the Period1 gene (Per1-/-) and the corresponding wildtype. In Per1-/- the amplitude in arylalkylamine-N-acetyltransferase expression was significantly elevated as compared to wildtype. In contrast, β-adrenergic receptor and inducible cAMP early repressor mRNA levels were not affected by the Period1-deficiency. This indicates that the molecular clockwork alters the amplitude of arylalkylamine-N-acetyltransferase expression. In vitro, pineal glands of Per1-/- mice showed a day night difference in arylalkylamine-N-acetyltransferase expression with high levels at night. This suggests that a deficient in Period1 elicits similar effects as the activation of the cAMP-signal transduction pathway in wildtype mice.
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Dr. Senckenbergische Anatomie, Institut für Anatomie II, Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany.
Pfeffer
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Korf
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von Gall
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D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D002940:Circadian Rhythm; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008550:Melatonin / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics*; D010870:Pineal Gland / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011943:Receptors, Adrenergic, beta / Q000096:biosynthesis / Q000235:genetics
C497411:Crem protein, mouse; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D051786:Cyclic AMP Response Element Modulator; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin