Journal
GENES & DEVELOPMENT
Volume 28, Issue 10, Pages 1101-1110Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.237511.114
Keywords
circadian clock; CaMKII; morning and evening oscillators; coupling of oscillators; SCN; CLOCK/BMAL1
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Funding
- Japan Society for the Promotion of Science (JSPS)
- MEXT, Japan
- JSPS Research Fellowships for Young Scientists
- Grants-in-Aid for Scientific Research [25117707, 23500478, 24390055, 25350978] Funding Source: KAKEN
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Daily behavioral rhythms in mammals are governed by the central circadian clock, located in the suprachiasmatic nucleus (SCN). The behavioral rhythms persist even in constant darkness, with a stable activity time due to coupling between two oscillators that determine the morning and evening activities. Accumulating evidence supports a prerequisite role for Ca2+ in the robust oscillation of the SCN, yet the underlying molecular mechanism remains elusive. Here, we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity is essential for not only the cellular oscillation but also synchronization among oscillators in the SCN. A kinase-dead mutation in mouse CaMKII alpha weakened the behavioral rhythmicity and elicited decoupling between the morning and evening activity rhythms, sometimes causing arrhythmicity. In the mutant SCN, the right and left nuclei showed uncoupled oscillations. Cellular and biochemical analyses revealed that Ca2+-calmodulin-CaMKII signaling contributes to activation of E-box-dependent gene expression through promoting dimerization of circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like protein 1 (BMAL1). These results demonstrate a dual role of CaMKII as a component of cell-autonomous clockwork and as a synchronizer integrating circadian behavioral activities.
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