Attenuated desensitization of β-adrenergic receptor by water-soluble N-nitrosamines that induce S-nitrosylation without NO release

Noriko Makita, Yoji Kabasawa, Yuko Otani, Firman, Junichiro Sato, Makiko Hashimoto, Michio Nakaya, Hiroaki Nishihara, Masaomi Nangaku, Hitoshi Kurose, Tomohiko Ohwada, Taroh Iiri

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14 Citations (Scopus)

Abstract

Rationale: The clinical problem of loss of β-adrenergic receptor (β-AR) response, both in the pathogenesis of heart failure and during therapeutic application of β-agonists, is attributable, at least in part, to desensitization, internalization, and downregulation of the receptors. In the regulation of β-AR signaling, G protein-coupled receptor kinase 2 (GRK2) primarily phosphorylates agonist-occupied β-ARs, and this modification promotes desensitization, internalization, and downregulation of β-ARs. It has been demonstrated that GRK2 is inhibited by its S-nitrosylation. However, compounds that induce S-nitrosylation, such as S-nitrosoglutathione, simultaneously generate NO, which has been demonstrated to operate for cardiovascular protection. Objective: We examine whether S-nitrosylation without NO generation inhibits desensitization of β2-AR by GRK2. We thus aim to synthesize compounds that specifically induce S-nitrosylation. Methods and Results: We have developed water-soluble N-nitrosamines that have S-nitrosylating activity but lack NO-generating activity. These compounds, at least partly, rescue β-AR from desensitization in HEK 293 cells expressing FLAG-tagged human β2-AR and in rat cardiac myocytes. They inhibit isoproterenol-dependent phosphorylation and internalization of β2-AR. Indeed, they nitrosylate GRK2 in vitro and in cells, and their S-nitrosylation of GRK2 likely underlies their inhibition of β2-AR desensitization. Conclusions: Compounds that induce S-nitrosylation without NO release inhibit GRK2 and attenuate β2-AR desensitization. Developing water-soluble drugs that specifically induce S-nitrosylation may be a promising therapeutic strategy for heart failure.

Original languageEnglish
Pages (from-to)327-334
Number of pages8
JournalCirculation research
Volume112
Issue number2
DOIs
Publication statusPublished - Jan 18 2013

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Makita, N., Kabasawa, Y., Otani, Y., Firman, Sato, J., Hashimoto, M., Nakaya, M., Nishihara, H., Nangaku, M., Kurose, H., Ohwada, T., & Iiri, T. (2013). Attenuated desensitization of β-adrenergic receptor by water-soluble N-nitrosamines that induce S-nitrosylation without NO release. Circulation research, 112(2), 327-334. https://doi.org/10.1161/CIRCRESAHA.112.277665