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

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.