title: A TRPC1-mediated increase in store-operated Ca2+ entry is required for the proliferation of adult hippocampal neural progenitor cells.
abstract: Adult hippocampal neurogenesis plays an important role in brain function and neurological diseases. Adult neural progenitor cell (aNPC) proliferation is a critical first step in hippocampal neurogenesis. However, the mechanisms that modulate aNPC proliferation have not been fully identified. Ample evidence has demonstrated that cell proliferation is dependent on the intracellular Ca(2+) concentration. We hypothesized that store-operated Ca(2+) channels (SOCs), which are ubiquitously expressed in all cell types, participate in aNPC proliferation. We found that store-operated Ca(2+) entry (SOCE) was involved in the proliferation of aNPCs and that 2-APB, Gd(3+) and SKF96365, antagonists of SOCE and canonical transient receptor potential (TRPC), respectively, inhibited the increase in SOCE and aNPC proliferation. We therefore analyzed the expression of TRPCs in aNPCs and showed that TRPC1 is the most significantly upregulated member under proliferative conditions. Interestingly, knockdown of TRPC1 and using an antibody against TRPC1 markedly reduced the degree of SOCE and aNPC proliferation. In parallel, we observed the suppression of aNPC proliferation was found to be associated with cell cycle arrest in G0/G1 phase. Furthermore, gene expression microarray analysis revealed a selective up- or downregulation of 10 genes in aNPCs following TRPC1 silencing. Knockdown of Orai1 or STIM1 also induced a significant inhibition of SOCE and proliferation in aNPCs, and all three proteins were colocalized in the plasma membrane region of cells. Together, these results indicate that SOCE represents a principal mechanism regulating the proliferation of aNPCs and that TRPC1 is an essential component of this pathway. This discovery may be important in improving adult hippocampal neurogenesis and treating cognitive deficits.
authors.affiliation: Department of Occupational Health, Third Military Medical University, Shapingba District, Chongqing, China.
authors.forename: Maoquan
authors.initials: M
authors.lastname: Li
authors.forename: Chunhai
authors.initials: C
authors.lastname: Chen
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D059585:G1 Phase Cell Cycle Checkpoints; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D015220:Calcium Channels; D007093:Imidazoles; D008562:Membrane Glycoproteins; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium