Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Extracellular Space/*metabolism ; Glutathione/*metabolism ; Receptors, Calcium-Sensing/*metabolism; Animals ; Biomarkers ; Calcium/chemistry ; Calcium/metabolism ; Cysteine/analogs & derivatives ; Glutathione/analogs & derivatives ; Glutathione/biosynthesis ; Glutathione/chemistry ; Glutathione Disulfide ; Humans ; Molecular Structure ; Organ Specificity ; Oxidation-Reduction ; Protein Binding ; Receptors, Calcium-Sensing/chemistry ; Receptors, Calcium-Sensing/genetics ; Structure-Activity Relationship

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.

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Keywords: L-cysteine-glutathione disulfide; calcium-sensing receptor; glutathione; ligand-binding; oxidized glutathione; receptor-binding

0 (Biomarkers)
0 (Receptors, Calcium-Sensing)
89TEL00G6V (cysteine-glutathione disulfide)
GAN16C9B8O (Glutathione)
K848JZ4886 (Cysteine)
SY7Q814VUP (Calcium)
ULW86O013H (Glutathione Disulfide)

Date Created: 20220121 Date Completed: 20220207 Latest Revision: 20220207

20231215

PMC8776003

10.3390/ijms23020717

35054903