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Molecular Neurobiology

, Volume 54, Issue 8, pp 5768–5779 | Cite as

Activation of Transient Receptor Potential Vanilloid 4 Promotes the Proliferation of Stem Cells in the Adult Hippocampal Dentate Gyrus

  • Yujing Tian
  • Mengwen Qi
  • Zhiwen Hong
  • Yingchun Li
  • Yibiao Yuan
  • Yimei Du
  • Lei ChenEmail author
  • Ling Chen
Article

Abstract

Neurogenesis plays an important role in adult hippocampal function, and this process can be modulated by intracellular calcium. The activation of transient receptor potential vanilloid 4 (TRPV4) induces an increase in intracellular calcium concentration, but whether neurogenesis can be modulated by TRPV4 activation remains unclear. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days enhanced the proliferation of stem cells in the hippocampal dentate gyrus (DG) of adult mice without affecting neurite growth, differentiation, or survival of newborn cells. GSK1016790A induced increases in the hippocampal protein levels of cyclin-dependent kinase (CDK) 6, CDK2, cyclin E1, and cyclin A2 but did not affect CDK4 and cyclin D1 expression. The phosphorylation of retinoblastoma protein (Rb) in hippocampi was enhanced in GSK1016790A-injected mice compared with control mice. Moreover, hippocampal protein levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation were enhanced by GSK1016790A. Finally, GSK1016790A-enhanced proliferation was markedly blocked by a MAPK/ERK kinase or p38 MAPK antagonist (U0126 or SB203580, respectively). The increased protein levels of CDK2 and CDK6, as well as those of cyclin E1 and cyclin A2, in GSK1016790A-injected mice were substantially reduced by co-injection of U0126 or SB203580. We conclude that TRPV4 activation results in the proliferation of stem cells in the adult hippocampal DG, which is likely mediated through ERK1/2 and p38 MAPK signaling to increase the expression of CDKs (CDK6 and CDK2) and cyclins (cyclin E1 and A2), phosphorylate Rb consequently, and accelerate the cell cycle ultimately.

Keywords

Transient receptor potential vanilloid 4 Neurogenesis Stem cell proliferation Calcium ERK signaling p38 MAPK signaling 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81571270 and 31271206 to Lei Chen and 81470421 to Yimei Du) and Qing Lan Project of Jiangsu province (2014–2017) to Lei Chen.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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ESM 1

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High resolution image (TIFF 183 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yujing Tian
    • 1
  • Mengwen Qi
    • 1
  • Zhiwen Hong
    • 1
  • Yingchun Li
    • 1
  • Yibiao Yuan
    • 2
  • Yimei Du
    • 3
  • Lei Chen
    • 1
    Email author
  • Ling Chen
    • 1
  1. 1.Department of PhysiologyNanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.The Laboratory Center for Basic Medical SciencesNanjing Medical UniversityNanjingPeople’s Republic of China
  3. 3.Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China

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