Mechanisms underlying the neuronal calcium sensor-1-evoked enhancement of exocytosis in PC12 cells

被引:79
作者
Koizumi, S
Rosa, P
Willars, GB
Challiss, RAJ
Taverna, E
Francolini, M
Bootman, MD
Lipp, P
Inoue, K
Roder, J
Jeromin, A
机构
[1] Natl Inst Hlth Sci, Sect Neuropharmacol, Div Pharmacol, Setagaya Ku, Tokyo 1588501, Japan
[2] Univ Milan, Dept Pharmacol, Inst Neurosci Cellular & Mol Pharmacol, I-20129 Milan, Italy
[3] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England
[4] Babraham Inst, Mol Signalling Lab, Cambridge CB2 4AT, England
[5] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada
关键词
D O I
10.1074/jbc.M201132200
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
Neuronal calcium sensor-1 (NCS-1) or the originally identified homologue frequenin belongs to a superfamily of EF-hand calcium binding proteins. Although NCS-1 is thought to enhance synaptic efficacy or exocytosis mainly by activating ion channel function, the detailed molecular basis for the enhancement is still a matter of debate. Here, mechanisms underlying the NCS-1-evoked enhancement of exocytosis were investigated using PC12 cells overexpressing NCS-1. NCS-1 was found to have a broad distribution in the cells being partially distributed in the cytosol and associated to vesicles and tubular-like structures. Biochemical and immunohistochemical studies indicated that NCS-1 partially colocalized with the light synaptic vesicle marker synaptophysin. When stimulated with UTP or bradykinin, agonists to phospholipase C-linked receptors, NCS-1 enhanced the agonist-mediated elementary and global Ca2+ signaling and increased the levels of downstream signals of phosphatidylinositol 4-kinase. NCS-1 enhanced the UTP-evoked exocytosis but not the depolarization-evoked Ca2+ responses or exocytosis, suggesting that the enhancement by NCS-1 should involve phospholipase C-linked receptor-mediated signals rather than the Ca2+ channels or exocytotic machinery per se. Taken together, NCS-1 enhances phosphoinositide turnover, resulting in enhancement of Ca2+ signaling and exocytosis. This is a novel regulatory mechanism of exocytosis that might involve the activation of phosphatidylinositol 4-kinase.
引用
收藏
页码:30315 / 30324
页数:10
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