Caveolin-1 alters the pattern of cytoplasmic Ca2+ oscillations and Ca2+-dependent gene expression by enhancing leukotriene receptor desensitization

Abstract

Cytoplasmic Ca2+ 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 C 4. The Ca2+ oscillations arise from regenerative Ca 2+ release from inositol 1,4,5-trisphosphate-sensitive stores followed by Ca2+ entry through store-operated Ca2+ channels, and the latter selectively activate the Ca2+-dependent transcription factor NFAT. The cysteinyl leukotriene type I receptors desensitize through negative feedback by protein kinase C, which terminates the oscillatory Ca2+ response. Here, we show that the scaffolding protein caveolin-1 has a profound effect on receptor-driven Ca2+ signals and downstream gene expression. Overexpression of caveolin-1 increased receptor-phospholipase C coupling, resulting in initially larger Ca2+ release transients of longer duration but which then ran down quickly. NFAT-activated gene expression, triggered in response to the Ca2+ 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 Ca2+ release in the presence of caveolin-1 activated protein kinase C, which accelerated homologous desensitization of the leukotriene receptor and thereby terminated the oscillatory Ca2+ response. Our results reveal that caveolin-1 is a bimodal regulator of receptor-dependent Ca2+ signaling, which fine-tunes the spatial and temporal profile of the Ca2+ rise and thereby its ability to activate the NFAT pathway. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.