Caveolin-1 alters the pattern of cytoplasmic Ca2+ oscillations and Ca2+-dependent gene expression by enhancing leukotriene receptor desensitization.
Bottom Line: Here, we show that the scaffolding protein caveolin-1 has a profound effect on receptor-driven Ca(2+) signals and downstream gene expression.Mutagenesis studies revealed that these effects required a functional scaffolding domain within caveolin-1.Our results reveal that caveolin-1 is a bimodal regulator of receptor-dependent Ca(2+) signaling, which fine-tunes the spatial and temporal profile of the Ca(2+) rise and thereby its ability to activate the NFAT pathway.
Affiliation: From the Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom and.Show MeSH
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Mentions: If caveolin-1 increases receptor-phospholipase C coupling, two predictions are that, first, InsP3 levels should increase more following stimulation in the presence of caveolin-1 than in wild type cells, and second, less Ca2+ should remain within the InsP3-sensitive store after the Ca2+ oscillations have run down in cells expressing caveolin-1. Using the GFP-PHD construct as a means for monitoring InsP3 levels in individual cells (15–17), we found that stimulation with LTC4 for 5 min resulted in a modest decrease in the membrane/cytosol ratio of GFP-PHD (decrease of 24.5 ± 1.7%; Fig. 3, A and B), and this was slightly more pronounced when caveolin-1-RFP was expressed (31.2 ± 1.4%, p < 0.05; Fig. 3, A and B). To test the second prediction, we stimulated cells with LTC4 in the absence of external Ca2+, and then once the oscillations had stopped, we applied thapsigargin in Ca2+-free solution to estimate how much Ca2+ remained within the store (Fig. 3C). The thapsigargin-mobilizable Ca2+ pool was significantly reduced in cells expressing caveolin-1-GFP (Fig. 3D, p < 0.01).
Affiliation: From the Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom and.