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Proc. Natl. Acad. Sci. USA, November 27, 2024 | https://doi.org/10.1073/pnas.2409773121
CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum
Jung-Mi Choi 1, Rakshya Acharya 1, Hye Lim Cha 1, Kwang-Wook Lee 1, Jewoo Seo 2, Esther Yang 3, Hyun Kim 3, Jong Hyuk Yoon 4, Da-Young Chang 5, Sung-Soo Kim 1, Sang Jeong Kim 2, Lutz Birnbaumer 6 7 *, Haeyoung Suh-Kim 1 5 8 *
1Department of Anatomy, Ajou University School of Medicine, Suwon 16499, South Korea.
2Department Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea.
3Department of Anatomy, College of Medicine, Korea University, Seoul 02841, Korea.
4Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, South Korea.
5Research Center, CELLeBRAIN Co., Ltd., Suwon 16681, South Korea.
6Institute of Biomedical Research, School of Biomedical Sciences, Catholic University of Argentina, Buenos Aires C1107AFF, Argentina.
7Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
8Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon 16499, Korea.
2Department Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea.
3Department of Anatomy, College of Medicine, Korea University, Seoul 02841, Korea.
4Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, South Korea.
5Research Center, CELLeBRAIN Co., Ltd., Suwon 16681, South Korea.
6Institute of Biomedical Research, School of Biomedical Sciences, Catholic University of Argentina, Buenos Aires C1107AFF, Argentina.
7Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
8Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon 16499, Korea.
*Corresponding authors: correspondence to Lutz Birnbaumer or Haeyoung Suh-Kim
Abstract
GNAO1 encodes the alpha subunit of the heterotrimeric Go protein. Despite being the most abundant G protein at synapses, the role of Go in the brain remains unclear, primarily because of the high mortality associated with developmental and epileptic encephalopathy (DEE) 17 in Gnao1 mutated animals. Here, we conducted proteomic analyses with a brain synaptosomal fraction to investigate the Go-interactome and then generated a non-DEE model using Gli1CreERT2 mice to selectively knockout (KO) the presynaptic Gαo within cerebellum. Our findings revealed that Gαo interacts with multiple proteins involved in neurotransmitter release, as well as cannabinoid receptor type 1 (CB1R), a key Gi/o-coupled receptor in presynaptic terminals. In Gnao1 KO mice, synapse formation was reduced in the cerebellum with a concomitant reduction in depolarization-induced suppression of excitation, a manifestation of CB1R-mediated synaptic plasticity found in the cerebellum. These mice displayed motor deficits in rotarod, grip strength, gait, and beam balance tests. Our results suggest that Go plays a critical role in regulating neurotransmitter releases at the presynaptic terminals and its absence in the entire brain may contribute to DEE pathogenesis. This study also provides valuable insights into the signaling pathways in the brain from a Go-dependent perspective.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-29)
- 국내(교신)+국외 연구진
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