Postsynaptic competition between calcineurin and PKA regulates mammalian sleep–wake cycles

Yimeng Wang, Siyu Cao, Daisuke Tone, Hiroshi Fujishima, Rikuhiro G. Yamada, Rei-ichiro Ohno, Shoi Shi, Kyoko Matsuzawa, Saori Yada, Mari Kaneko, Hirokazu Sakamoto, Taichi Onishi, Maki Ukai-Tadenuma, Hideki Ukai, Carina Hanashima, Kenzo Hirose, Hiroshi Kiyonari, Kenta Sumiyama, Koji L. Ode and Hiroki R. Ueda ()
Additional contact information
Yimeng Wang: The University of Tokyo
Siyu Cao: The University of Tokyo
Daisuke Tone: The University of Tokyo
Hiroshi Fujishima: RIKEN Center for Biosystems Dynamics Research
Rikuhiro G. Yamada: RIKEN Center for Biosystems Dynamics Research
Rei-ichiro Ohno: The University of Tokyo
Shoi Shi: The University of Tokyo
Kyoko Matsuzawa: RIKEN Center for Biosystems Dynamics Research
Saori Yada: The University of Tokyo
Mari Kaneko: RIKEN Center for Biosystems Dynamics Research
Hirokazu Sakamoto: The University of Tokyo
Taichi Onishi: The University of Tokyo
Maki Ukai-Tadenuma: RIKEN Center for Biosystems Dynamics Research
Hideki Ukai: RIKEN Center for Biosystems Dynamics Research
Carina Hanashima: Waseda University
Kenzo Hirose: The University of Tokyo
Hiroshi Kiyonari: RIKEN Center for Biosystems Dynamics Research
Kenta Sumiyama: RIKEN Center for Biosystems Dynamics Research
Koji L. Ode: The University of Tokyo
Hiroki R. Ueda: The University of Tokyo

Nature, 2024, vol. 636, issue 8042, 412-421

Abstract: Abstract The phosphorylation of synaptic proteins is a significant biochemical reaction that controls the sleep–wake cycle in mammals1–3. Protein phosphorylation in vivo is reversibly regulated by kinases and phosphatases. In this study, we investigate a pair of kinases and phosphatases that reciprocally regulate sleep duration. First, we perform a comprehensive screen of protein kinase A (PKA) and phosphoprotein phosphatase (PPP) family genes by generating 40 gene knockout mouse lines using prenatal and postnatal CRISPR targeting. We identify a regulatory subunit of PKA (Prkar2b), a regulatory subunit of protein phosphatase 1 (PP1; Pppr1r9b) and catalytic and regulatory subunits of calcineurin (also known as PP2B) (Ppp3ca and Ppp3r1) as sleep control genes. Using adeno-associated virus (AAV)-mediated stimulation of PKA and PP1–calcineurin activities, we show that PKA is a wake-promoting kinase, whereas PP1 and calcineurin function as sleep-promoting phosphatases. The importance of these phosphatases in sleep regulation is supported by the marked changes in sleep duration associated with their increased and decreased activities, ranging from approximately 17.3 h per day (PP1 expression) to 4.3 h per day (postnatal CRISPR targeting of calcineurin). Localization signals to the excitatory post-synapse are necessary for these phosphatases to exert their sleep-promoting effects. Furthermore, the wake-promoting effect of PKA localized to the excitatory post-synapse negated the sleep-promoting effect of PP1–calcineurin. These findings indicate that PKA and PP1–calcineurin have competing functions in sleep regulation at excitatory post-synapses.

Date: 2024
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DOI: 10.1038/s41586-024-08132-2

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