Redox-dependent internalization ofthe purinergic P2Y6 receptor limits colitis progression

Kazuhiro Nishiyama, Akiyuki Nishimura, Kakeru Shimoda, Tomohiro Tanaka, Yuri Kato, Takahiro Shibata, Hiroshi Tanaka, Hitoshi Kurose, Yasu Taka Azuma, Hideshi Ihara, Yoshito Kumagai, Takaaki Akaike, Philip Eaton, Koji Uchida, Motohiro Nishida

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


After ligand stimulation, many G protein-coupled receptors (GPCRs) undergo β-arrestin-dependent desensitization, during which they are internalized and either degraded or recycled to the plasma membrane. Some GPCRs are not subject to this type of desensitization because they lack the residues required to interact with β-arrestins. We identified a mechanism of redox-dependent alternative internalization (REDAI) that promotes the internalization and degradation of the purinergic P2Y6receptor (P2Y2R). Synthetic and natural compounds containing electrophilic isothiocyanate groups covalently modified P2Y6R at Cys220, which promoted the ubiquitylation of Lys137and receptor internalization and degradation in various mouse and human cultured cell lines. Endogenous electrophiles also promoted ligand-dependent P2Y6R internalization and degradation. P2Y6R is highly abundant in inflammatory cells and promotes the pathogenesis of colitis. Deficiency in P2Y6R protected mice against experimentally induced colitis, and mice expressing a form of P2Y6R in which Cys220was mutated to nonmodifiable serine were more sensitive to the induction of colitis. Several other GPCRs, including A2BAR, contain cysteine and lysine residues at the appropriate positions to mediate REDAI, and isothiocyanate stimulated the internalization of A2BAR and of a form of P2Y2R with insertions of the appropriate residues. Thus, endogenous and exogenous electrophiles may limit colitis progression through cysteine modification of P2Y6R and may also mediate internalization of other GPCRs.

Original languageEnglish
Article numbereabj0644
JournalScience Signaling
Issue number716
Publication statusPublished - Jan 11 2022

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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