2. Academic Validation
  3. ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude

ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude

  • Commun Biol. 2022 Jul 28;5(1):750. doi: 10.1038/s42003-022-03725-x.
Huilin Li  # 1,  Jiali Ou  # 1,  Yaqun Li 1,  Niannian Xu 2 3,  Qing Li 2,  Ping Wu 4,  Chao Peng 4,  Yun-Chi Tang 5,  Hung-Chun Chang 6 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 3 Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China.
  • 4 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China.
  • 5 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. yctang@sibs.ac.cn.
  • 6 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China. hcchang@ion.ac.cn.
  • 7 Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China. hcchang@ion.ac.cn.
  • # Contributed equally.
PMID: 35902736 DOI: 10.1038/s42003-022-03725-x
Abstract

Circadian dysregulation associates with numerous diseases including metabolic dysfunction, sleep disorder, depression and aging. Given that declined circadian amplitude is a trait commonly found with compromised health, interventions that design in precluding circadian amplitude from dampening will aid to mitigate complex, circadian-related diseases. Here we identify a neurogenic small molecule ISX-9 that is able to support persistent and higher amplitude of circadian oscillations. ISX-9 improves diurnal metabolic rhythms in middle-aged mice. Moreover, the ISX-9-treated mice show better sleep homeostasis with increased delta power during the day time and higher locomotive activity in the dark period. ISX-9 augments CaMKIIδ expression and increases BMAL1 activity via eliciting CaMKIIδ-mediated phosphorylation on BMAL1 residues S513/S515/S516, accordingly composes a positive feedback effect on enhancing circadian amplitude. CaMKIIδ-targeting, and the use of ISX-9 may serve as decent choices for treating circadian-related disorders.

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