Extracellular
glutathione (GSH) and
oxidized glutathione (
GSSG) can modulate the function of the extracellular
calcium sensing receptor (CaSR). The CaSR has a binding pocket in the extracellular domain of CaSR large enough to bind either GSH or
GSSG, as well as the naturally occurring oxidized derivative
L-cysteine glutathione disulfide (
CySSG) and the compound cysteinyl
glutathione (CysGSH). Modeling the binding energies (ΔG) of
CySSG and CysGSH to CaSR reveals that both
cysteine derivatives may have greater affinities for CaSR than either GSH or
GSSG. GSH,
CySSG, and
GSSG are found in circulation in mammals and, among the three,
CySSG is more affected by HIV/
AIDs and aging than either GSH or
GSSG. The beta-
carbon linkage of
cysteine in CysGSH may model a new class of calcimimetics, exemplified by
etelcalcetide. Circulating glutathionergic compounds, particularly
CySSG, may mediate
calcium-regulatory responses via receptor-binding to CaSR in a variety of organs, including parathyroids, kidneys, and bones. Receptor-mediated actions of glutathionergics may thus
complement their roles in redox regulation and detoxification. The glutathionergic binding site(s) on CaSR are suggested to be a target for development of drugs that can be used in treating kidney and other diseases whose mechanisms involve CaSR dysregulation.