Receptor Redox Complexities
The observation that excreted thioredoxin-1 (Trx1), which reduces transiently formed disulfide bonds, may alter receptor function acting at CD30, a member of the tumor necrosis factor receptor (TNFR) superfamily and may, in this way, link oxidative stress to lymphocyte function (1), is important for a number of reasons. This action of Trx1 required the presence of a source of reducing equivalents, suggesting that there may have been some previous oxidation of free thiol groups. This observation, therefore, suggested the catchy title “Receptors Redox Receptor Regulation Revealed” (2).
The sensitivity of some G protein-coupled receptors to S-nitrosothiols suggests the presence of at least one or more free thiol groups (3). The varying reactivities of these free thiols also suggest very complex mechanisms that regulate their redox states and reactivities with other thiol-containing molecules. For example, the finding that unlike the P2Y1 receptor, which has 2 essential disulfide bridges in its extracellular domains, the P2Y12 receptor has 2 free cysteines in its extracellular domains (Cys17 and Cys270), both of which are the targets of thiol reagents and the active metabolites of clopidogrel, which forms disulfide bridges with Cys17 and/or Cys270 in the P2Y12 receptor and thereby inactivates the receptor (4).
The presence of disulfide bonds, which could be reduced under the right redox conditions, and the possible binding of endogenous ligands to biological receptors suggest just some of the difficulties involved in characterizing cellular receptors in their native and functional states. From our work, we’ve deduced that there must be at least one free thiol group that modulates ligand binding and receptor activation (5,6). From the complex redox states (thiol-disulfide exchange, sulfenic acid (R-SOH), sulfinic acids (R-SO2H) and sulfonic acids (R-SO3H), thiol chelation of transition metals (chiefly Zn2+, Mn2+, and Cu2+), and S-nitrosylation, we begin to see the complexity associated with studying and understanding the reactivities of free thiols in many important cellular and biological systems.