Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 16, Pages 6662-6667Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1017640108
Keywords
angiotensin receptor; Ca2+ signaling; calcineurin; signaling complex; posttranslational modification
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Naito Foundation
- Mochida Memorial Foundation
- Grants-in-Aid for Scientific Research [20117013, 23659042, 23229008, 22590083, 22689003, 22136008] Funding Source: KAKEN
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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 kappa B (NF-kappa B) 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-kappa B in the cytosol through flavin-binding domain, which was indispensable for the locally generated NO-mediated S-nitrosylation of p65 at Cys38. beta-Arrestins anchored the formation of p65/I kappa B alpha/beta-arrestins/iNOS quaternary complex. The S-nitrosylated p65 resulted in decreases in NF-kappa B 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.
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