Methylxanthines Modulate Circadian Period Length Independently of the Action of Phosphodiesterase

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dc.contributor.authorOlivares-Yanez, Consuelo
dc.contributor.authorAlessandri, Maria P.
dc.contributor.authorSalas, Loreto
dc.contributor.authorLarrondo, Luis F.
dc.date.accessioned2025-01-20T20:10:50Z
dc.date.available2025-01-20T20:10:50Z
dc.date.issued2023
dc.description.abstractIn 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) (Delta 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.
dc.description.abstractEvidence 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.
dc.fuente.origenWOS
dc.identifier.doi10.1128/spectrum.03727-22
dc.identifier.issn2165-0497
dc.identifier.urihttps://doi.org/10.1128/spectrum.03727-22
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92099
dc.identifier.wosidWOS:001000548100001
dc.issue.numero4
dc.language.isoen
dc.revistaMicrobiology spectrum
dc.rightsacceso restringido
dc.subjectmethylxanthines
dc.subjectcircadian clock
dc.subjectphosphodiesterase
dc.subjectcAMP
dc.subjectprotein kinase A
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleMethylxanthines Modulate Circadian Period Length Independently of the Action of Phosphodiesterase
dc.typeartículo
dc.volumen11
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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