Novel functions of small conductance Ca2+-activated K+ channel in enhanced cell proliferation by ATP in brain endothelial cells

被引:38
作者
Yamazaki, Daiju
Aoyama, Mineyoshi
Ohya, Susumu
Muraki, Katsuhiko
Asai, Kiyofumi
Imaizumi, Yuji
机构
[1] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, Mizuho Ku, Nagoya, Aichi 4678603, Japan
[2] Nagoya City Univ, Grad Sch Med Sci, Dept Mol Neurobiol, Mizuho Ku, Nagoya, Aichi 4678601, Japan
[3] Aichi Gakuin Univ, Sch Pharm, Cell Signaling & Ion Channel Res Grp, Chikusa Ku, Nagoya, Aichi 4648650, Japan
关键词
D O I
10.1074/jbc.M603917200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Brain capillary endothelial cells (BCECs) form the blood-brain barrier (BBB), which is essential for maintaining homeostasis of the brain. Net cellular turnover, which results from the balance between cell death and proliferation, is important in maintaining BBB homeostasis. Here we report a novel mechanism that underlies ATP-induced cell proliferation in t-BBEC 117, a cell line derived from bovine brain endothelial cells. Application of 0.1-30 mu M ATP to t-BBEC 117 concentration-dependently increased intracellular Ca2+ concentration ([Ca2+](i)) in two phases: an initial transient phase and a later and smaller sustained one. These two phases of [Ca2+](i) rise were mainly due to Ca2+ release and sustained Ca2+ influx, respectively. The pretreatment with apamin, a selective blocker of small conductance Ca2+-activated K+ channels (SK), significantly reduced both the [Ca2+](i) increase and K+ current induced by ATP. Transcripts corresponding to P2Yx, SK2, and transient receptor potential channels were detected in t-BBEC 117. Knock down of SK2 protein, which was the predominant Ca2+-activated K+ channel expressed in t-BBEC 117, by siRNA significantly reduced both the sustained phase of the [Ca2+](i) rise and the K+ current induced by ATP. Cell proliferation was increased significantly by the presence of the stable ATP analogue ATP gamma S. This effect was blunted by UCL1684, a synthesized SK blocker. In conclusion, in brain endothelial cells ATP-induced [Ca2+](i) rise activates SK2 current, and the subsequent membrane hyperpolarization enhances Ca2+ entry presumably through transient receptor potential channels. This positive feedback mechanism can account for the augmented cell proliferation by ATP.
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收藏
页码:38430 / 38439
页数:10
相关论文
共 45 条
[1]   Astrocyte-endothelial interactions at the blood-brain barrier [J].
Abbott, NJ ;
Rönnbäck, L ;
Hansson, E .
NATURE REVIEWS NEUROSCIENCE, 2006, 7 (01) :41-53
[2]   Astrocyte-endothelial interactions and blood-brain barrier permeability [J].
Abbott, NJ .
JOURNAL OF ANATOMY, 2002, 200 (06) :629-638
[3]   Expression and functional role of bTRPC1 channels in native endothelial cells [J].
Antoniotti, S ;
Lovisolo, D ;
Pla, AF ;
Munaron, L .
FEBS LETTERS, 2002, 510 (03) :189-195
[4]   P2Y2-receptor-mediated activation of a contralateral, lanthanide-sensitive calcium entry pathway in the human airway epithelium [J].
Bahra, P ;
Mesher, J ;
Li, S ;
Poll, CT ;
Danahay, H .
BRITISH JOURNAL OF PHARMACOLOGY, 2004, 143 (01) :91-98
[5]  
Beech DJ, 2004, J PHYSIOL-LONDON, V559, P685, DOI 10.1113/jphysiol.2004.068734
[6]   TRPC1: store-operated channel and more [J].
Beech, DJ .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2005, 451 (01) :53-60
[7]   The versatility and universality of calcium signalling [J].
Berridge, MJ ;
Lipp, P ;
Bootman, MD .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2000, 1 (01) :11-21
[8]   Calcium - a life and death signal [J].
Berridge, MJ ;
Bootman, MD ;
Lipp, P .
NATURE, 1998, 395 (6703) :645-648
[9]   Astrocyte-endothelial cell calcium signals conveyed by two signalling pathways [J].
Braet, K ;
Paemeleire, K ;
D'Herde, K ;
Sanderson, MJ ;
Leybaert, L .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 13 (01) :79-91
[10]   Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation [J].
Cheong, A ;
Bingham, AJ ;
Li, J ;
Kumar, B ;
Sukumar, P ;
Munsch, C ;
Buckley, NJ ;
Neylon, CB ;
Porter, KE ;
Beech, DJ ;
Wood, IC .
MOLECULAR CELL, 2005, 20 (01) :45-52