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 () and Shigeki Kiyonaka ()
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Kento Ojima: Nagoya University
Wataru Kakegawa: Keio University School of Medicine
Tokiwa Yamasaki: Keio University School of Medicine
Yuta Miura: Nagoya University
Masayuki Itoh: Keio University School of Medicine
Yukiko Michibata: Kyoto University
Ryou Kubota: Kyoto University
Tomohiro Doura: Nagoya University
Eriko Miura: Keio University School of Medicine
Hiroshi Nonaka: Kyoto University
Seiya Mizuno: University of Tsukuba
Satoru Takahashi: University of Tsukuba
Michisuke Yuzaki: Keio University School of Medicine
Itaru Hamachi: Kyoto University
Shigeki Kiyonaka: Nagoya University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30828-0

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