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2015 ; 30
(2
): 155-60
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Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene
rhythms in the suprachiasmatic nucleus
#MMPMID25724980
Besing RC
; Paul JR
; Hablitz LM
; Rogers CO
; Johnson RL
; Young ME
; Gamble KL
J Biol Rhythms
2015[Apr]; 30
(2
): 155-60
PMID25724980
show ga
The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the
cellular level via transcriptional-translational feedback loops comprising clock
genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a
serine/threonine kinase, phosphorylates at least 5 core clock proteins and shows
diurnal variation in phosphorylation state (inactivation) of the GSK3? isoform.
Whether phosphorylation of the other primary isoform (GSK3?) varies across the
subjective day-night cycle is unknown. The purpose of this study was to determine
if the endogenous rhythm of GSK3 (? and ?) phosphorylation is critical for
rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular
clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (? and
?) was observed in the SCN from wild-type mice housed in constant darkness for 2
weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity
of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3
with 20 µM CHIR-99021 enhanced the amplitude and shortened the period of
PER2::luciferase rhythms in organotypic SCN slice cultures. These results support
the model that GSK3 activity status is regulated by the circadian clock and that
GSK3 feeds back to regulate the molecular clock amplitude in the SCN.