TRPC5 channel-Caveolin-1-eNOS signalplexes coordinate interplay between Ca2+ and NO signals in endothelial cells
日本薬理学会年会要旨集 =(2021)
摘要
The cell signaling molecules nitric oxide (NO) and Ca2+ regulate diverse biological processes through closely coordinated activities. However, signaling protein complexes that underlie the interplay between Ca2+ and NO pathways remain unclear in many tissues and cell types. Here we demonstrate the physical and functional interaction of the receptor-activated Ca2+-permeable TRPC5 channel with Ca2+-dependent endothelial NO synthase (eNOS) in vascular endothelial cells as well as HEK293 cells overexpressing these proteins. Upon stimulation of G-protein-coupled ATP receptors, Ca2+ influx via receptor-activated TRPC5 channels elicits NO production from eNOS, which in turn induces secondary activation of TRPC5 channels via cysteine S-nitrosylation. TRPC5 is co-immunoprecipitated with eNOS and the scaffolding protein caveolin-1. Mutations in the caveolin-1-binding domains of TRPC5 impair their association and disrupt Ca2+ influx and NO production, suggesting that caveolin-1 is the scaffold that enables TRPC5 and eNOS to assemble into the signaling complex. Interestingly, ATP receptor-activated Ca2+ influx dissociates eNOS from caveolin-1 but enhances the association between TRPC5 and eNOS at the plasma membrane. This may relieve eNOS from negative regulation by caveolin-1 and promote the production of NO in the vicinity of TRPC5, leading to an efficient secondary activation of TRPC5 via S-nitrosylation. Thus, our study provides evidence that the TRPC5 channel-cavolin-1-eNOS complex dynamically coordinates NO and Ca2+ signaling in vascular endothelial cells.
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关键词
endothelial cells,channel-caveolin
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