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PMID: 21464294 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 108 ·No. 16 ·2011-04-19 ·Pages 6662-7

Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim KM, Ide T, Sato Y, Inoue K, Kurose H

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(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.

MeSH Terms
Adenosine Triphosphate/pharmacology Animals Down-Regulation Gene Expression Regulation, Enzymologic/drug effects,genetics HEK293 Cells Humans Male Mice Mice, Knockout Myocardium/metabolism NFATC Transcription Factors/genetics,metabolism Nitric Oxide/genetics,metabolism Nitric Oxide Synthase Type II/genetics,metabolism Phosphorylation/drug effects,genetics Rats Receptor, Angiotensin, Type 1/biosynthesis,genetics Receptors, Purinergic P2Y2/genetics,metabolism Transcription Factor RelA/genetics,metabolism
Chemicals
NFATC Transcription Factors Nfatc1 protein, mouse Nfatc3 protein, mouse Receptor, Angiotensin, Type 1 Receptors, Purinergic P2Y2 Rela protein, mouse Transcription Factor RelA Nitric Oxide Adenosine Triphosphate Nitric Oxide Synthase Type II Nos2 protein, mouse
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Nishida Motohiro
Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Ogushi Mariko
Suda Reiko
Toyotaka Miyuki
Saiki Shota
Kitajima Naoyuki
Nakaya Michio
Kim Kyeong-Man
Ide Tomomi
Sato Yoji
Inoue Kazuhide
Kurose Hitoshi
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1017640108
Published
2011-04-19
Epub
2011-00-04
Pages
6662-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3080971
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.1017640108 PMC Full Text View journal details
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