The mechanism of transmembrane S-nitrosothiol transport

AUTOR(ES)

Zhang, Yanhong

FONTE

National Academy of Sciences

RESUMO

S-nitrosothiols have been suggested to play an important role in nitric oxide (NO)-mediated biological events. However, the mechanisms by which an S-nitrosothiol (or the S-nitroso functional group) is transferred across cell membrane are still poorly understood. We have demonstrated previously that the degradation of S-nitrosoglutathione (GSNO) by cells absolutely required the presence of cystine in the extracellular medium and proposed a mechanism that involved the reduction of cystine to cysteine, followed by the reaction of cysteine with GSNO to form S-nitrosocysteine (CysNO), mixed disulfides, and nitrosyl anion. In the present study we have assessed the effect of cystine on the transfer of the S-nitroso functional group from the extracellular to the intracellular space. Using RAW 264.7 cells, we found that the presence of l-cystine enhanced GSNO-dependent S-nitrosothiol uptake, increasing the intracellular S-nitrosothiol level from ≈60 pmol/mg of protein to ≈3 nmol/mg of protein. The uptake seems to depend on the reduction of l-cystine to l-cysteine, which involves the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}x_{c}^{-}\end{equation*}\end{document} amino acid transport system, the transnitrosation between GSNO and l-cysteine to form l-CysNO, and uptake of l-CysNO via amino acid transport system L. Compared with GSNO, (Z)-1-[N-(3-ammoniopropyl)-N-[4-(3-aminopropylammonio)butyl]-amino]diazen-1-ium-1,2-diolate, an NO donor, is much less effective at intracellular S-nitrosothiol formation in the presence of l-cystine or l-cysteine, suggesting that the biochemical changes that occur after exposure of cells to S-nitrosothiol, with respect to thiol chemistry, are distinctly different from those observed with NO.

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