Methylxanthines Modulate Circadian Period Length Independently of the Action of Phosphodiesterase.

Autor:	Olivares-Yañez C; ANID-Millennium Science Initiative Program, Millennium Institute for Integrative Biology (iBio), Santiago, Chile.; Centro de Biotecnología Vegetal, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile., Alessandri MP; ANID-Millennium Science Initiative Program, Millennium Institute for Integrative Biology (iBio), Santiago, Chile.; Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Salas L; ANID-Millennium Science Initiative Program, Millennium Institute for Integrative Biology (iBio), Santiago, Chile.; Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Larrondo LF; ANID-Millennium Science Initiative Program, Millennium Institute for Integrative Biology (iBio), Santiago, Chile.; Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Jazyk:	angličtina
Zdroj:	Microbiology spectrum [Microbiol Spectr] 2023 Aug 17; Vol. 11 (4), pp. e0372722. Date of Electronic Publication: 2023 Jun 05.
DOI:	10.1128/spectrum.03727-22
Abstrakt:	In Neurospora crassa, caffeine and other methylxanthines are known to inhibit phosphodiesterase (PDE) activity, leading to augmented cAMP levels. In this organism, it has also been shown that the addition of these drugs significantly lengthens the circadian period, as seen by conidiation rhythms. Utilizing in vivo bioluminescence reporters, pharmacological inhibitors, and cAMP analogs, we revisited the effect of methylxanthines and the role of cAMP signaling in the Neurospora clockworks. We observed that caffeine, like all tested methylxanthines, led to significant period lengthening, visualized with both core-clock transcriptional and translational reporters. Remarkably, this phenotype is still observed when phosphodiesterase (PDE) activity is genetically or chemically (via 3-isobutyl-1-methylxanthine) abrogated. Likewise, methylxanthines still exert a period effect in several cAMP signaling pathway mutants, including adenylate cyclase ( cr-1 ) and protein kinase A (PKA) (Δ pkac-1 ) mutants, suggesting that these drugs lead to circadian phenotypes through mechanisms different from the canonical PDE-cAMP-PKA signaling axis. Thus, this study highlights the strong impact of methylxanthines on circadian period in Neurospora , albeit the exact mechanisms somehow remain elusive. IMPORTANCE Evidence from diverse organisms show that caffeine causes changes in the circadian clock, causing period lengthening. The fungus Neurospora crassa is no exception; here, several methylxanthines such as caffeine, theophylline, and aminophylline cause period lengthening in a concentration-dependent manner. Although methylxanthines are expected to inhibit phosphodiesterase activity, we were able to show by genetic and pharmacological means that these drugs exert their effects through a different mechanism. Moreover, our results indicate that increases in cAMP levels and changes in PKA activity do not impact the circadian period and therefore are not part of underlying effects of methylxanthine. These results set the stage for future analyses dissecting the molecular mechanisms by which these drugs dramatically modify the circadian period. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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