Extracellular cysteine (Cys)/cystine (CySS) redox regulates metabotropic glutamate receptor 5 activity

Extracellular cysteine (Cys)/cystine (CySS) redox potential (E_h) has been shown to regulate diverse biological processes, including enzyme catalysis, gene expression, and signaling pathways for cell proliferation and apoptosis, and is sensitive to aging, smoking, and other host factors. However, the effects of extracellular Cys/CySS redox on the nervous system remain unknown. In this study, we explored the role of extracellular Cys/CySS E_h in metabotropic glutamate receptor 5 (mGlu5) activation to understand the mechanism of its regulation of nerve cell growth and activation. We showed that the oxidized Cys/CySS redox state (0 mV) in C6 glial cells induced a significant increase in mGlu5-mediated phosphorylation of extracellular signal-regulated kinase (ERK), blocked by an inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK), U0126, a nonpermeant alkylating agent, 4-acetamide-4′-maleimidylstilbene-2,2′-disulfonic acid (AMS), and a specific mGlu5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), respectively. ERK phosphorylation under oxidized extracellular Cys/CySS E_h was confirmed in mGlu5-overexpressed human embryonic kidney 293 (HEK293) cells. Oxidized extracellular Cys/CySS E_h also stimulated the generation of intracellular reactive oxygen species (ROS) involved in the phosphorylation of ERK by mGlu5. Moreover, activation of mGlu5 by oxidized extracellular Cys/CySS E_h was found to affect expression of NF-κB and inducible nitric oxide synthase (iNOS). The results also showed that extracellular Cys/CySS E_h involved in the activation of mGlu5 controlled cell death and cell activation in neurotoxicity. In addition, plasma Cys/CySS E_h was found to be associated with the process of Parkinson’s disease (PD) in a rotenone-induced rat model of PD together with dietary deficiency and supplementation of sulfur amino acid (SAA). The effects of extracellular Cys/CySS E_h on SAA dietary deficiency in the rotenone-induced rat model of PD was almost blocked by MPEP pretreatment, further indicating that oxidized extracellular Cys/CySS E_h plays a role in mGlu5 activity. Taken together, the results indicate that mGlu5 can be activated by extracellular Cys/CySS redox in nerve cells, which possibly contributes to the process of PD. These in vitro and in vivo findings may aid in the development of potential new nutritional strategies that could assist in slowing the degeneration of PD.