title: Activation of Transient Receptor Potential Vanilloid 4 Promotes the Proliferation of Stem Cells in the Adult Hippocampal Dentate Gyrus.
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.
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Mengwen
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
authors.forename: Yibiao
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People's Republic of China. chenl@njmu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D013234:Stem Cells / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Calcium; ERK signaling; Neurogenesis; Stem cell proliferation; Transient receptor potential vanilloid 4; p38 MAPK signaling