Effects of inhibitors of the lipo-oxygenase family of enzymes on the store-operated calcium current/CRAC in rat basophilic leukaemia cells

被引:27
作者
Glitsch, MD [1 ]
Bakowski, D [1 ]
Parekh, AB [1 ]
机构
[1] Univ Oxford, Dept Physiol, Lab Mol & Cellular Signalling, Oxford OX1 3PT, England
来源
JOURNAL OF PHYSIOLOGY-LONDON | 2002年 / 539卷 / 01期
基金
英国惠康基金;
关键词
D O I
10.1113/jphysiol.2001.012826
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In non-excitable cells, the major Ca2+ entry pathway is the store-operated pathway in which emptying of intracellular Ca2+ stores activates Ca2+ channels in the plasma membrane. In many cell types, store-operated influx gives rise to a Ca2+-selective current called I-CRAC (Ca2+ release-activated Ca2+ current). Using both the whole-cell patch clamp technique to measure I-CRAC directly and fluorescent Ca2+ imaging, we have examined the role of the lipo-oxygenase pathway in the activation of store-operated Ca2+ entry in the RBL-1 rat basophilic leukaemia cell-line. Pretreatment with a variety of structurally distinct lipo-oxygenase inhibitors all reduced the extent of I-CRAC, whereas inhibition of the cyclo-oxygenase enzymes was without effect. The inhibition was still seen in the presence of the broad protein kinase blocker staurosporine, or when Na+ was used as the charge carrier through CRAC channels. The lipo-oxygenase blockers released Ca2+ from intracellular stores but this was not associated with subsequent Ca2+ entry. Lipo-oxygenase blockers also reduced both the amount of Ca2+ that could subsequently be released by the combination of thapsigargin and ionomycin in Ca2+-free solution and the Ca2+ influx component that occurred when external Ca2+ was re-admitted. The inhibitors were much less effective if applied after I-CRAC had been activated. This inhibition of I-CRAC could not be rescued by dialysis with 5(S)-hydroxyperoxyeicosa-6E,8Z,11Z,14Z,tetraenoic acid (5-HPETE), the first product of the 5-lipo-oxygenase pathway. Our findings indicate that exposure to pharmacological tools that inhibit the lipo-oxygenase enzymes all decrease the extent of activation of the current. Our results raise the possibility that a lipo-oxygenase might be involved in the activation of I-CRAC. Alternative explanations are also discussed.
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收藏
页码:93 / 106
页数:14
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