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

Motohiro Nishida, Mariko Ogushi, Reiko Suda, Miyuki Toyotaka, Shota Saiki, Naoyuki Kitajima, Michio Nakaya, Kyeong Man Kim, Tomomi Ide, Yoji Sato, Kazuhide Inoue, Hitoshi Kurose

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

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 1R) density through NO-mediated S-nitrosylation of nuclear factor κB (NF-κB) in rat cardiac .broblasts. Stimulation of purinergic P2Y2 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 .avin-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 AT1R density. In pressure-overloaded mouse hearts, ATP released from cardiomyocytes led to decrease in AT 1R density through iNOS-mediated S-nitrosylation of p65. These results show a unique regulatory mechanism of heterologous regulation of GPCRs in which cysteine modi.cation of transcriptional factor rather than protein phosphorylation plays essential roles.

Original languageEnglish
Pages (from-to)6662-6667
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number16
DOIs
Publication statusPublished - Apr 19 2011

All Science Journal Classification (ASJC) codes

  • General

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