Role of RSNOs in Platelet Function

One of the most studied functions of PDI is its ability to catalyze isomerization and rearrangement of disulfide bonds (Eq. (14)) in the ER contributing to a proper folding of nascent proteins (Novia et al., 1992). 

PDI contains a C-terminal tetrapeptide sequence known as the endoplasmic retention signal, KDEL. This anchor mediates the interaction between plasma membrane and membranes of the Golgi apparatus via a KDEL receptor. The PDI KDEL receptor complex is recycled back into the endoplasmic reticulum (Xiao et al., 1999). It is thought that a saturation of the retention mechanism results in the secretion of PDI which is deposited on the cell membrane and stabilized by electrostatic interactions (Terada et al, 1995). The secreted PDI is termed cell surface PDI (csPDI) 

Detwiler and co-workers were the first to demonstrate a role for csPDI in platelet physiology (Chen et al, 1995 Essex et al, 1995). Essex and co-workers (1999, 2001) and Hogg and co-workers (Burgess et al., 2000) showed that the inactivation of csPDI with anti-PDI antibodies and thiol alkylating agents inhibited platelet activation and aggregation. Recent studies have identified two distinct activities for csPDI. 

The second activity, termed denitrosation (Eq. (15)), is catalyzed by the reduced form of the same active site thiols that are involved in the thiol-disulfide exchange activity of the enzyme (Zai et al, 1999 Ramachandran et al. 2001 Raturi and Mutus, 2004). In this process csPDI catalyzes the release of NO from RSNOs. 

Therefore, RSNOs appear to regulate PDI-dependent adhesion by competitively inhibiting integrin-ligand disulfide bond formation and, in the process, producing NO which prevents further activation of recruited platelets via the GC/G-kinase route. 

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