Circadian binding activity of AP-1, a regulator of the arylalkylamine N-acetyltransferase gene in the rat pineal gland, depends on circadian Fra-2, c-Jun, and Jun-D expression and is regulated by the clock's zeitgebers.

Abstract

The daily rhythm in circulating melatonin is driven by a circadian rhythm in the expression of the arylalkylamine N:-acetyltransferase gene in the rat pineal gland. Turning off expression of this gene at the end of night is believed to involve inhibitory transcription factors, among which Fos-related antigen 2 (Fra-2) appears as a good candidate. Circadian rhythms in the expression of three proteins of activating protein-1 (AP-1) complexes, namely, Fra-2, c-Jun, and Jun-D, are shown here to account for circadian variations in AP-1 binding activity. Quantitative variations in the Fra-2 component over the circadian cycle were associated with qualitative variations in protein isoforms. Destruction of the suprachiasmatic nucleus resulted in decreased nocturnal AP-1 activity, showing that AP-1 circadian rhythm is driven by this nucleus. Exposure to light during subjective night and administration of a serotonin 5-HT(1A)/5-HT(7) receptor agonist during subjective day, respectively, induced a 50% decrease and a 50% increase in both AP-1 and Fra-2 expression. These effects were impaired by suprachiasmatic nucleus lesions. These data show that pineal AP-1 binding activity, which results from Fra-2 expression, can be modulated by light and serotonin through the suprachiasmatic nucleus according to a "phase dependence" that is characteristic of the rhythm of clock sensitivity to both zeitgebers.