Drug discovery targeting redox-dependent alternative internalization (REDAI) of GPCRs

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  • Nishiyama Kazuhiro
    Department of Physiology, Graduate School of Pharmaceutical Sciences Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
  • Nishimura Akiyuki
    Department of Physiology, Graduate School of Pharmaceutical Sciences Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS), Okazaki 444-8787, Japan
  • Kato Yuri
    Department of Physiology, Graduate School of Pharmaceutical Sciences Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
  • Shimoda Kakeru
    National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS), Okazaki 444-8787, Japan
  • Nishida Motohiro
    Department of Physiology, Graduate School of Pharmaceutical Sciences Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS), Okazaki 444-8787, Japan

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Other Title
  • GPCRのレドックス依存的内在化（REDAI）を標的とする創薬

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<p>G protein-coupled receptors (GPCRs) play pivotal roles in converting physicochemical stimuli due to environmental changes to intracellular responses. After ligand stimulation, many GPCRs are desensitized and then recycled or degraded through b-arrestin-dependent internalization, an important process to maintain protein quality control of GPCRs. However, it is unknown how GPCRs with low β-arrestin sensitivity are controlled. Here we unmasked a b-arrestin-independent GPCR internalization, named Redox-dependent alternative internalization (REDAI), using b-arrestin-resistant purinergic P2Y6 receptor (P2Y6R). Natural isothiocyanates (ITCs) covalently bind with Cys220 in the intracellular 3rd loop of P2Y6R, and promote internalization and degradation of P2Y6R through ubiquitination of Lys137 in the 2nd loop. P2Y6R is highly expressed in macrophage and pathologically contributes to the development of colitis in mice. Endogenous electrophiles, such as S-nitrosoglutathione, also induce P2Y6R degradation leading to anti-inflammation in macrophages. Prevention of Cys220 modification on P2Y6R resulted in aggravation of the colitis. Accordingly, targeting REDAI on GPCRs will be a breakthrough strategy for the prevention and treatment of inflammatory diseases.</p>

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