CaMKII is essential for the cellular clock and coupling between morning and evening behavioral rhythms.
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 Ca(2+) in the robust oscillation of the SCN, yet the underlying molecular mechanism remains elusive. Here, we show that Ca(2+)/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 CaMKIIα 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 Ca(2+)-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.
Department of Biosciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Naohiro
N
Kon
Department of Chronomedicine, Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
Tomoko
T
Yoshikawa
Department of Chronomedicine, Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
Sato
S
Honma
Department of Information Physiology, National Institute for Physiological Sciences, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan;
Yoko
Y
Yamagata
Department of Biosciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Hikari
H
Yoshitane
Department of Biosciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Kimiko
K
Shimizu
Department of Biosciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Yasunori
Y
Sugiyama
Department of Biosciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Chihiro
C
Hara
Department of Life Sciences, Faculty of Agriculture, Kagawa University, Miki-cho, Kagawa 761-0795, Japan.
Isamu
I
Kameshita
Department of Chronomedicine, Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan;
Ken-ichi
K
Honma
Department of Biosciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Yoshitaka
Y
Fukada
D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics*; D056926:CLOCK Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D041681:NIH 3T3 Cells; D009474:Neurons / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction
D056930:ARNTL Transcription Factors; D004791:Enzyme Inhibitors; D056926:CLOCK Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
CLOCK/BMAL1; CaMKII; SCN; circadian clock; coupling of oscillators; morning and evening oscillators