Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Alvarez-Buylla A, Garcia-Verdugo JM (2002) Neurogenesis in adult subventricular zone. J Neurosci 22:629–634

    CAS  PubMed  Google Scholar 

  2. Balu DT, Lucki I (2009) Adult hippocampal neurogenesis: regulation, function implications and contribution to disease pathology. Neurosci Biobehav Rev 33:232–252

    Article  PubMed  Google Scholar 

  3. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signaling. Nat Rev Mol Cell Biol 1:11–21

    Article  CAS  PubMed  Google Scholar 

  4. Capiod T (2013) The need for calcium channels in cell proliferation. Recent Pat Anticancer Drug Discov 8:4–17

    Article  CAS  PubMed  Google Scholar 

  5. Guo Z, Shi F, Zhang L, Zhang H, Yang J, Li B, Jia J, Wang X, Wang X (2010) Critical role of L-type voltage-dependent Ca2+ channels in neural progenitor cell proliferation induced by hypoxia. Neurosci Lett 478:156–160

    Article  CAS  PubMed  Google Scholar 

  6. Bunk EC, König HG, Prehn JH, Kirby BP (2014) Effect of the N-methyl-D-aspartate NR2B subunit antagonist ifenprodil on precursor cell proliferation in the hippocampus. J Neurosci Res 92:679–691

    Article  CAS  PubMed  Google Scholar 

  7. Garcia-Elias A, Mrkonjić S, Jung C, Pardo-Pastor C, Vicente R, Valverde MA (2014) The TRPV4 channel. Handb Exp Pharmacol 222:293–319

    Article  CAS  PubMed  Google Scholar 

  8. Hatano N, Suzuki H, Itoh Y, Muraki K (2013) TRPV4 partially participates in proliferation of human brain capillary endothelia cells. Life Sci 92:317–324

    Article  CAS  PubMed  Google Scholar 

  9. Troidl C, Troidl K, Schierling W, Cai WJ, Nef H, Möllmann H, Kostin S, Schimanski S, Hammer L, Elsässer A, Schmitz-Rixen T, Schaper W (2009) Trpv4 induces collateral vessel growth during regeneration of the arterial circulation. J Cell Mol Med 13:2613–2621

    Article  PubMed  Google Scholar 

  10. Martin E, Dahan D, Cardouat G, Gillibert-Duplantier J, Marthan R, Savineau JP, Ducret T (2012) Involvement of TRPV1 and TRPV4 channels in migration of rat pulmonary arterial smooth muscle cells. Pflugers Arch 464:261–272

    Article  CAS  PubMed  Google Scholar 

  11. Li M, Chen C, Zhou Z, Xu S, Yu Z (2012) A TRPC1-mediated increase in store-operated Ca2+ entry is required for the proliferation of adult hippocampal neuronal progenitor cells. Cell Calcium 51:486–496

    Article  CAS  PubMed  Google Scholar 

  12. Thoppil RJ, Adapala RK, Cappelli HC, Kondeti V, Dudley AC, Gary Meszaros J, Paruchuri S, Thodeti CK (2015) TRPV4 channel activation selectively inhibits tumor endothelia cell proliferation. Sci Rep 5:14257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Song Y, Zhan L, Yu M, Huang C, Meng X, Ma T, Zhang L, Li J (2014) TRPV4 channel inhibits TGF-β1-induced proliferation of hepatic stellate cells. PLoS One 9:e101179

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jie P, Hong Z, Tian Y, Li Y, Lin L, Zhou L, Du Y, Chen L, Chen L (2015) Activation of transient receptor potential vanilloid 4 induces apoptosis in hippocampus through down-regulating PI3K/Akt and up-regulating p38 MAPK signaling pathways. Cell Death Dis 6:e1775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jie P, Lu Z, Hong Z, Li L, Zhou L, Li Y, Zhou R, Zhou Y, Du Y, Chen L, Chen L (2016) Activation of transient receptor potential vanilloid 4 is involved in neuronal injury in middle cerebral artery occlusion in mice. Mol Neurobiol 53:8–17

    Article  CAS  PubMed  Google Scholar 

  16. Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, Griswold DE (1996) Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther 279:1453–1461

    CAS  PubMed  Google Scholar 

  17. Duncia JV, Santella JB 3rd, Higley CA, Pitts WJ, Wityak J, Frietze WE, Rankin FW, Sun JH, Earl RA, Tabaka AC, Teleha CA, Blom KF, Favata MF, Manos EJ, Daulerio AJ, Stradley DA, Horiuchi K, Copeland RA, Scherle PA, Trzaskos JM, Magolda RL, Trainor GL, Wexler RR, Hobbs FW, Olson RE (1998) MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 8:2839–2844

    Article  CAS  PubMed  Google Scholar 

  18. Sha S, Xu J, ZH L, Hong J, WJ Q, Zhou JW, Chen L (2016) Lack of JWA enhances neurogenesis and long-term potentiation in hippocampal dentate gyrus leading to spatial cognitive potentiation. Mol Neurobiol 53:355–368

    Article  CAS  PubMed  Google Scholar 

  19. Wang C, Chen T, Li G, Zhou L, Sha S, Chen L (2015) Simvastatin prevents β-amyloid(25-35)-impaired neurogenesis in hippocampal dentate gyrus through α7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate. Neuropharmacology 97:122–132

    Article  CAS  PubMed  Google Scholar 

  20. Schutte B, Tinnemans MM, Pijpers GF, Lenders MH, Ramaekers FC (1995) Three parameter flow cytometric analysis for simultaneous detection of cytokeratin, proliferation associated antigens and DNA content. Cytometry 21:177–186

    Article  CAS  PubMed  Google Scholar 

  21. Cheffer A, Tárnok A, Ulrich H (2013) Cell cycle regulation during neurogenesis in the embryonic and adult brain. Stem Cell Rev 9:794–805

    Article  CAS  PubMed  Google Scholar 

  22. Miloso M, Scuteri A, Foudah D, Tredici G (2008) MAPKs as mediators of cell fate determination: an approach to neurodegenerative diseases. Curr Med Chem 15:538–548

    Article  CAS  PubMed  Google Scholar 

  23. Rao MS, Shetty AK (2004) Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur J Neurosci 19:234–246

    Article  PubMed  Google Scholar 

  24. Shibasaki K, Suzuki M, Mizuno A, Tominaga M (2007) Effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient receptor potential vanilloid 4. J Neurosci 27:1566–1575

    Article  CAS  PubMed  Google Scholar 

  25. Fiorio Pla A, Maric D, Brazer SC, Giacobini P, Liu X, Chang YH, Ambudkar IS, Barker JL (2005) Canonical transient receptor potential 1 plays a role in basic fibroblast growth factor (bFGF)/FGF receptor-1-induced Ca2+ entry and embryonic rat neural stem cell proliferation. J Neurosci 25:2687–2701

    Article  PubMed  Google Scholar 

  26. Wu X, Zagranichnaya TK, Gurda GT, Eves EM, Villereal ML (2004) A TRPC1/TRPC3-mediated increase in store-operated calcium entry is required for differentiation of H19-7 hippocampal neuronal cells. J Biol Chem 279:43392–43402

    Article  CAS  PubMed  Google Scholar 

  27. Ueda T, Shikano M, Kamiya T, Joh T, Ugawa S (2011) The TRPV4 channel is a novel regulator of intracellular Ca2+ in human esophageal epithelial cells. Am J Physiol Gastrointest Liver Physiol 301:G138–G147

    Article  CAS  PubMed  Google Scholar 

  28. Li L, Qu W, Zhou L, Lu Z, Jie P, Chen L, Chen L (2013) Activation of transient receptor potential vanilloid 4 increases NMDA-activated current in hippocampal pyramidal neurons. Front Cell Neurosci 7

  29. Kuang CY, Yu Y, Wang K, Qian DH, Den MY, Huang L (2012) Knockdown of transient receptor potential canonical-1 reduces the proliferation and migration of endothelial progenitor cells. Stem Cells Dev 21:487–496

    Article  CAS  PubMed  Google Scholar 

  30. Hanano T, Hara Y, Shi J, Morita H, Umebayashi C, Mori E, Sumimoto H, Ito Y, Mori Y, Inoue R (2004) Involvement of TRPM7 in cell growth as a spontaneously activated Ca2+ entry pathway in human retinoblastoma cells. J Pharmacol Sci 95:403–419

    Article  CAS  PubMed  Google Scholar 

  31. Yee NS, Zhou W, Liang IC (2011) Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer. Dis Model Mech 4:240–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Duronio RJ, Xiong Y (2013) Signaling pathways that control cell proliferation. Cold Spring Harb Perspect Biol 5:a008904

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nayak PS, Wang Y, Najrana T, Priolo LM, Rios M, Shaw SK, Sanchez-Esteban J (2015) Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells. Respir Res 16:60

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chen Y, Kanju P, Fang Q, Lee SH, Parekh PK, Lee W, Moore C, Brenner D, Gereau RW 4th, Wang F, Liedtke W (2014) TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. Pain 155:2662–2672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Segond von Banchet G, Boettger MK, König C, Iwakura Y, Bräuer R, Schaible HG (2013) Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia. Mol Cell Neurosci 52:152–160

    Article  CAS  PubMed  Google Scholar 

  36. Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, Cohen P, Khandekar MJ, Boström P, Mepani RJ, Laznik D, Kamenecka TM, Song X, Liedtke W, Mootha VK, Puigserver P, Griffin PR, Clapham DE, Spiegelman BM (2012) TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 151:96–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chambard JC, Lefloch R, Pouysségur J (2007) ERK implication in cell cycle regulation. Biochim Biophys Acta 1773:1299–1310

    Article  CAS  PubMed  Google Scholar 

  38. Dougherty JD, Garcia AD, Nakano I, Livingstone M, Norris B, Polakiewicz R, Wexler EM, Sofroniew MV, Kornblum HI, Geschwind DH (2005) PBK/TOPK, a proliferating neural progenitor-specific mitogen-activated protein kinase kinase. J Neurosci 25:10773–10785

    Article  CAS  PubMed  Google Scholar 

  39. Baron W, Metz B, Bansal R, Hoekstra D, de Vries H (2000) PDGF and FGF-2 signaling in oligodendrocyte progenitor cells: regulation of proliferation and differentiation by multiple intracellular signaling pathways. Mol Cell Neurosci 15:314–329

    Article  CAS  PubMed  Google Scholar 

  40. Zhang D, Guo M, Zhang W, XY L (2011) Adiponectin stimulates proliferation of adult hippocampal neural stem/progenitor cells through activation of p38 mitogen-activated protein kinase (p38MAPK)/glycogen synthase kinase 3β (GSK-3β)/β-catenin signaling cascade. J Biol Chem 286:44913–44920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ (2010) Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet 42:170–174

    Article  PubMed  Google Scholar 

  42. Fecto F, Shi Y, Huda R, Martina M, Siddique T, Deng HX (2011) Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. J Biol Chem 286:17281–17291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jang Y, Jung J, Kim H, Oh J, Jeon JH, Jung S, Kim KT, Cho H, Yang DJ, Kim SM, Kim IB, Song MR, Oh U (2012) Axonal neuropathy-associated TRPV4 regulates neurotrophic factor-derived axonal growth. J Biol Chem 287:6014–6024

    Article  CAS  PubMed  Google Scholar 

  44. Curtis MA, Low VF, Faull RL (2012) Neurogenesis and progenitor cells in the adult human brain: a comparison between hippocampal andsubventricular progenitor proliferation. Dev Neurobiol 72:990–1005

    Article  PubMed  Google Scholar 

  45. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 101:343–347

    Article  CAS  PubMed  Google Scholar 

  46. Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, Greenberg DA (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 98:4710–4715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People’s Republic of China

    Yujing Tian, Mengwen Qi, Zhiwen Hong, Yingchun Li, Lei Chen & Ling Chen

  2. The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, 210029, People’s Republic of China

    Yibiao Yuan

  3. 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

    Yimei Du

Authors
  1. Yujing Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mengwen Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiwen Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingchun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yibiao Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yimei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ling Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lei Chen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tian, Y., Qi, M., Hong, Z. et al. Activation of Transient Receptor Potential Vanilloid 4 Promotes the Proliferation of Stem Cells in the Adult Hippocampal Dentate Gyrus. Mol Neurobiol 54, 5768–5779 (2017). https://doi.org/10.1007/s12035-016-0113-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-0113-y

Keywords

Search

Navigation