Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kappaB

Cross-talk between G protein-coupled receptor (GPCR) signaling pathways serves to fine tune cellular responsiveness by neurohumoral factors. Accumulating evidence has implicated nitric oxide (NO)-based signaling downstream of GPCRs, but the molecular details are unknown. Here, we show that adenosine...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-04, Vol.108 (16), p.6662
Main Authors: Nishida, Motohiro, Ogushi, Mariko, Suda, Reiko, Toyotaka, Miyuki, Saiki, Shota, Kitajima, Naoyuki, Nakaya, Michio, Kim, Kyeong-Man, Ide, Tomomi, Sato, Yoji, Inoue, Kazuhide, Kurose, Hitoshi
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - pharmacology
Animals
Down-Regulation
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - genetics
HEK293 Cells
Humans
Male
Mice
Mice, Knockout
Myocardium - metabolism
NFATC Transcription Factors - genetics
NFATC Transcription Factors - metabolism
Nitric Oxide - genetics
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - genetics
Nitric Oxide Synthase Type II - metabolism
Phosphorylation - drug effects
Phosphorylation - genetics
Rats
Receptor, Angiotensin, Type 1 - biosynthesis
Receptor, Angiotensin, Type 1 - genetics
Receptors, Purinergic P2Y2 - genetics
Receptors, Purinergic P2Y2 - metabolism
Transcription Factor RelA - genetics
Transcription Factor RelA - metabolism
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Summary:Cross-talk between G protein-coupled receptor (GPCR) signaling pathways serves to fine tune cellular responsiveness by neurohumoral factors. Accumulating evidence has implicated nitric oxide (NO)-based signaling downstream of GPCRs, but the molecular details are unknown. Here, we show that adenosine triphosphate (ATP) decreases angiotensin type 1 receptor (AT(1)R) density through NO-mediated S-nitrosylation of nuclear factor κB (NF-κB) in rat cardiac fibroblasts. Stimulation of purinergic P2Y(2) receptor by ATP increased expression of inducible NO synthase (iNOS) through activation of nuclear factor of activated T cells, NFATc1 and NFATc3. The ATP-induced iNOS interacted with p65 subunit of NF-κB in the cytosol through flavin-binding domain, which was indispensable for the locally generated NO-mediated S-nitrosylation of p65 at Cys38. β-Arrestins anchored the formation of p65/IκBα/β-arrestins/iNOS quaternary complex. The S-nitrosylated p65 resulted in decreases in NF-κB transcriptional activity and AT(1)R density. In pressure-overloaded mouse hearts, ATP released from cardiomyocytes led to decrease in AT(1)R density through iNOS-mediated S-nitrosylation of p65. These results show a unique regulatory mechanism of heterologous regulation of GPCRs in which cysteine modification of transcriptional factor rather than protein phosphorylation plays essential roles.
ISSN:1091-6490
DOI:10.1073/pnas.1017640108