Protein disulfide-isomerase mediates delivery of nitric oxide redox derivatives into platelets

Susannah E Bell , Chirag M Shah , Michael P Gordge (1)

1 Biomedical Science

S-nitrosothiol compounds are important mediators of NO signalling and can give rise to various redox derivatives of NO: Nitrosonium cation (NO +}), nitroxyl anion (NO -}) and NO ·} radical. Several enzymes and transporters have been implicated in the intracellular delivery of NO from S-nitrosothiols. In this study we have investigated the role of glutathione peroxidase (GPx), the L-amino acid transporter (L-AT) system and protein disulphide isomerase (PDI) in the delivery of NO redox derivatives into human platelets. Washed human platelets were treated with inhibitors of GPx, L-AT and PDI prior to exposure to donors of NO redox derivatives (S-nitrosoglutathione, Angeli‘s salt and Diethylamine NONOate). Rapid delivery of NO-related signalling into platelets was monitored by cGMP accumulation and DAF-FM fluorescence. All NO redox donors produced both a cGMP response and DAF-FM fluorescence in target platelets. NO delivery was blocked by inhibition of PDI in a dose-dependent manner. In contrast, inhibition of GPx and L-AT had only a minimal effect on NO-related signalling. PDI activity is therefore required for the rapid delivery into platelets of NO-related signals from donors of all NO redox derivatives. GPx and the L-AT system appeared to be unimportant in rapid NO signalling by the compounds used in this study. This does not, however, exclude a possible role during exposure of cells to other S-nitrosothiol compounds, such as S-nitrosocysteine. These results further highlight the importance of PDI in mediating the action of a wide range of NO-related signals.

Mots clés: Life Sciences

Susannah E Bell, Chirag M Shah, Michael P Gordge. Protein disulfide-isomerase mediates delivery of nitric oxide redox derivatives into platelets. Biochemical Journal, 2006, 403 (2), pp.283-288. ⟨10.1042/BJ20061146⟩. ⟨hal-00478639⟩