Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue

Kento Ojima, Wataru Kakegawa, Tokiwa Yamasaki, Yuta Miura, Masayuki Itoh, Yukiko Michibata, Ryou Kubota, Tomohiro Doura, Eriko Miura, Hiroshi Nonaka, Seiya Mizuno, Satoru Takahashi, Michisuke Yuzaki, Itaru Hamachi, Shigeki Kiyonaka

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Direct activation of cell-surface receptors is highly desirable for elucidating their physiological roles. A potential approach for cell-type-specific activation of a receptor subtype is chemogenetics, in which both point mutagenesis of the receptors and designed ligands are used. However, ligand-binding properties are affected in most cases. Here, we developed a chemogenetic method for direct activation of metabotropic glutamate receptor 1 (mGlu1), which plays essential roles in cerebellar functions in the brain. Our screening identified a mGlu1 mutant, mGlu1(N264H), that was activated directly by palladium complexes. A palladium complex showing low cytotoxicity successfully activated mGlu1 in mGlu1(N264H) knock-in mice, revealing that activation of endogenous mGlu1 is sufficient to evoke the critical cellular mechanism of synaptic plasticity, a basis of motor learning in the cerebellum. Moreover, cell-type-specific activation of mGlu1 was demonstrated successfully using adeno-associated viruses in mice, which shows the potential utility of this chemogenetics for clarifying the physiological roles of mGlu1 in a cell-type-specific manner.

Original languageEnglish
Article number3167
JournalNature communications
Volume13
Issue number1
DOIs
Publication statusPublished - 2022 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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