Research on disease treatment targeting oxidative modification and zinc modification of GPCR

Abstract

G protein-coupled receptors (GPCRs) are membrane proteins involved in a variety of physiological functions and disease progression. Research on GPCRs is fiercely competitive around the world using structural and molecular biological methods, and many drugs targeting GPCRs have been produced. However, most of them are based on the control mechanism by agonists and antagonists, and there have been few studies that delve into the diversity of receptor responses. In this study, we revealed that Cys residues in the intracellular third loop of GPCRs serve as target sites for oxidation and sulfuration, triggering internalization and proteolysis of GPCRs. We also found that transient receptor potential canonical (TRPC) 6 channels, which are permeable to metal ions (mainly Zn²⁺ and Fe²⁺), enhanced signal responses through zinc modification of GPCRs. In this presentation, I would like to introduce our recent findings and future directions for drug discovery research for inflammatory bowel disease targeting redox modification of GPCRs and drug discovery research for heart failure targeting receptor-operated cation channels.