title: Caveolin-1 alters the pattern of cytoplasmic Ca2+ oscillations and Ca2+-dependent gene expression by enhancing leukotriene receptor desensitization.
abstract: Cytoplasmic Ca(2+) oscillations constitute a widespread signaling mode and are often generated in response to stimulation of G protein-coupled receptors that activate phospholipase C. In mast cells, repetitive Ca(2+) oscillations can be evoked by modest activation of cysteinyl leukotriene type I receptors by the physiological trigger, leukotriene C4. The Ca(2+) oscillations arise from regenerative Ca(2+) release from inositol 1,4,5-trisphosphate-sensitive stores followed by Ca(2+) entry through store-operated Ca(2+) channels, and the latter selectively activate the Ca(2+)-dependent transcription factor NFAT. The cysteinyl leukotriene type I receptors desensitize through negative feedback by protein kinase C, which terminates the oscillatory Ca(2+) response. Here, we show that the scaffolding protein caveolin-1 has a profound effect on receptor-driven Ca(2+) signals and downstream gene expression. Overexpression of caveolin-1 increased receptor-phospholipase C coupling, resulting in initially larger Ca(2+) release transients of longer duration but which then ran down quickly. NFAT-activated gene expression, triggered in response to the Ca(2+) signal, was also reduced by caveolin-1. Mutagenesis studies revealed that these effects required a functional scaffolding domain within caveolin-1. Mechanistically, the increase in Ca(2+) release in the presence of caveolin-1 activated protein kinase C, which accelerated homologous desensitization of the leukotriene receptor and thereby terminated the oscillatory Ca(2+) response. 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.
authors.affiliation: From the Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom and.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Yeh
authors.affiliation: the Department of Physiology, National Cheng Kung University Medical College, Tainan and Department of Life Science, Tunghai University, Taichung 40704, Taiwan.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.affiliation: From the Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom and anant.parekh@dpag.ox.ac.uk.
authors.forename: Anant B
authors.initials: AB
authors.lastname: Parekh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1; D018077:Receptors, Leukotriene; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium
keywords: Calcium Signaling; Caveolin; G Protein-coupled Receptor (GPCR); Gene Transcription; Receptor Desensitization
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