Fig. 9

Schematic representation of feedback loops that connect ER Ca²⁺ loading, GSH influx, and oxidative protein folding. Hyper-oxidizing conditions in the ER (orange box) due to peak oxidative protein folding leads to Ca²⁺ depletion via opening of IP3R calcium channels and inhibition of SERCA pumps. Ca²⁺ depletion can in turn activate a GSH transporter (yellow box), which will restore the proper steady-state ER redox environment (green box). Conversely, hyper-reducing conditions in the ER (blue box) lower GSH influx via increased [Ca²⁺]_ER, thereby rescuing steady-state ER redox and commensurate oxidative protein folding. These feedback mechanisms regulate the pace of oxidative protein folding and contribute to the robustness of ER luminal redox balance