PDF and cAMP enhance PER stability in Drosophila clock neurons

Apr 8, 2014Proceedings of the National Academy of Sciences of the United States of America

PDF and cAMP increase stability of the PER protein in fruit fly internal clock cells

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Abstract

pdf(01) (pdf-null) Drosophila exhibit mostly arrhythmic behavior or shortened circadian periods under constant darkness.

PDF is associated with the amplitude, synchrony, and pace of circadian rhythms in clock neurons.
The mutant period gene per(S) improves the arrhythmic phenotypes in pdf-null flies.
The period protein (PER) acts as a repressor of clock gene transcription, and PERS, a variant, has a significantly short half-life.
Elevated levels of cAMP and protein kinase A (PKA) activity are linked to increased stability of PER in both cultured cells and fly circadian neurons.
A light pulse results in more rapid degradation of PER in pdf-null neurons compared to wild-type neurons.
PDF enhances clock neuron synchrony by increasing cAMP and PKA, which stabilize PER and reduce clock speed in PDFR-containing neurons.

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The neuropeptide PDF is important for Drosophila circadian rhythms: pdf(01) (pdf-null) animals are mostly arrhythmic or short period in constant darkness and have an advanced activity peak in light-dark conditions. PDF contributes to the amplitude, synchrony, as well as the pace of circadian rhythms within clock neurons. PDF is known to increase cAMP levels in PDR receptor (PDFR)-containing neurons. However, there is no known connection of PDF or of cAMP with the Drosophila molecular clockworks. We discovered that the mutant period gene per(S) ameliorates the phenotypes of pdf-null flies. The period protein (PER) is a well-studied repressor of clock gene transcription, and the per(S) protein (PERS) has a markedly short half-life. The result therefore suggests that the PDF-mediated increase in cAMP might lengthen circadian period by directly enhancing PER stability. Indeed, increasing cAMP levels and cAMP-mediated protein kinase A (PKA) activity stabilizes PER, in S2 tissue culture cells and in fly circadian neurons. Adding PDF to fly brains in vitro has a similar effect. Consistent with these relationships, a light pulse causes more prominent PER degradation in pdf(01) circadian neurons than in wild-type neurons. The results indicate that PDF contributes to clock neuron synchrony by increasing cAMP and PKA, which enhance PER stability and decrease clock speed in intrinsically fast-paced PDFR-containing clock neurons. We further suggest that the more rapid degradation of PERS bypasses PKA regulation and makes the pace of clock neurons more uniform, allowing them to avoid much of the asynchrony caused by the absence of PDF.

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PDF and cAMP enhance PER stability in Drosophila clock neurons

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