| Voltage-activated K+ channels and membrane depolarization regulate accumulation of the cyclin-dependent kinase inhibitors p27(Kip1) and p21(CIP1) in glial progenitor cells. | |
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MedLine Citation:
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PMID: 10377348 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Neural cell development is regulated by membrane ion channel activity. We have previously demonstrated that cell membrane depolarization with veratridine or blockage of K+ channels with tetraethylammonium (TEA) inhibit oligodendrocyte progenitor (OP) proliferation and differentiation (); however the molecular events involved are largely unknown. Here we show that forskolin (FSK) and its derivative dideoxyforskolin (DFSK) block K+ channels in OPs and inhibit cell proliferation. The antiproliferative effects of TEA, FSK, DFSK, and veratridine were attributable to OP cell cycle arrest in G1 phase. In fact, (1) cyclin D accumulation in synchronized OP cells was not affected by K+ channel blockers or veratridine; (2) these agents prevented OP cell proliferation only if present during G1 phase; and (3) G1 blockers, such as rapamycin and deferoxamine, mimicked the anti-proliferative effects of K+ channel blockers. DFSK also prevented OP differentiation, whereas FSK had no effect. Blockage of K+ channels and membrane depolarization also caused accumulation of the cyclin-dependent kinase inhibitors p27(Kip1) and p21(CIP1) in OP cells. The antiproliferative effects of K+ channel blockers and veratridine were still present in OP cells isolated from INK4a-/- mice, lacking the cyclin-dependent kinase inhibitors p16(INK4a) and p19(ARF). Our results demonstrate that blockage of K+ channels and cell depolarization induce G1 arrest in the OP cell cycle through a mechanism that may involve p27(Kip1) and p21(CIP1) and further support the conclusion that OP cell cycle arrest and differentiation are two uncoupled events. |
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Authors:
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C A Ghiani; X Yuan; A M Eisen; P L Knutson; R A DePinho; C J McBain; V Gallo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 19 ISSN: 0270-6474 ISO Abbreviation: J. Neurosci. Publication Date: 1999 Jul |
Date Detail:
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Created Date: 1999-07-15 Completed Date: 1999-07-15 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 5380-92 Citation Subset: IM |
Affiliation:
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Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4495, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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8-Bromo Cyclic Adenosine Monophosphate
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pharmacology Animals Cell Cycle Proteins* Cell Division / drug effects Cell Lineage / drug effects Cerebellum / drug effects Cyclin D Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclins / metabolism* Deferoxamine / pharmacology Forskolin / analogs & derivatives, pharmacology Ion Channel Gating / drug effects Isoproterenol / pharmacology Membrane Potentials* / drug effects Mice Microtubule-Associated Proteins / metabolism* Oligodendroglia / cytology*, drug effects, metabolism Potassium / metabolism Potassium Channel Blockers Potassium Channels / physiology* Rats Rats, Sprague-Dawley Sirolimus / pharmacology Stem Cells / cytology*, drug effects, metabolism Tetraethylammonium / pharmacology Tumor Suppressor Proteins* Veratridine / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Cdkn1a protein, mouse; 0/Cdkn1a protein, rat; 0/Cdkn1b protein, mouse; 0/Cdkn1b protein, rat; 0/Cell Cycle Proteins; 0/Cyclin D; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Microtubule-Associated Proteins; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/Tumor Suppressor Proteins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 23583-48-4/8-Bromo Cyclic Adenosine Monophosphate; 53123-88-9/Sirolimus; 64657-18-7/1,9-dideoxyforskolin; 66-40-0/Tetraethylammonium; 66428-89-5/Forskolin; 70-51-9/Deferoxamine; 71-62-5/Veratridine; 7440-09-7/Potassium; 7683-59-2/Isoproterenol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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