Disrupting stroke-induced GAT-1-syntaxin1A interaction promotes functional recovery after stroke
Although stroke is a frequent cause of permanent disability, our ability to promote stroke recovery is limited. Here, we design a small-molecule stroke recovery promoting agent that works by dissociating γ-aminobutyric acid (GABA) transporter 1 (GAT-1) from syntaxin1A (Synt1A), a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein. Stroke induces an increase in GAT-1-Synt1A interaction in the subacute phase, a critical period for functional recovery. Uncoupling GAT-1-Synt1A reverses stroke-induced GAT-1 dysfunction and cortical excitability decline and enhances synaptic GABAergic inhibition and consequently cortical oscillations and network plasticity by facilitating the assembly of the SNARE complex at the synapse. Based on the molecular mechanism of GAT-1 binding to Synt1A, we design GAT-1-Synt1A blockers. Among them, ZLQ-3 exhibits the greatest potency. Intranasal use of ZLQ-3-1, a glycosylation product of ZLQ-3, substantially lessens impairments of sensorimotor and cognitive functions in rodent models. This compound, or its analogs, may serve as a promoting agent for stroke recovery.
Authors
- Na Li (ORCID: https://orcid.org/0000-0003-3246-0039)
- Yajuan Qin (ORCID: https://orcid.org/0000-0003-1223-9548)
- Feng Wu (ORCID: https://orcid.org/0000-0002-4459-5486)
- Tingyou Li (ORCID: https://orcid.org/0000-0002-4216-2206)
- Li‐Juan Zhu (ORCID: https://orcid.org/0000-0003-3478-1725)
- Chun‐Xia Luo (ORCID: https://orcid.org/0000-0002-9840-0402)
- Dong‐Ya Zhu (ORCID: https://orcid.org/0000-0002-2145-0225)
- Youming Hou (ORCID: https://orcid.org/0000-0002-5187-2816)
- Xiu-Mei Xu
- Lei Chang (ORCID: https://orcid.org/0000-0002-4508-3853)
- Mingyu Chen (ORCID: https://orcid.org/0000-0003-4469-1037)
- Yu‐Hui Lin (ORCID: https://orcid.org/0000-0003-2244-0587)
- Fan Gao (ORCID: https://orcid.org/0000-0002-5879-0362)
- Hai‐Yin Wu (ORCID: https://orcid.org/0000-0003-1765-5911)
- Chang-Jing Zhang
Institutions
- Southeast University (CN)
- Nanjing Medical University (CN)
- Nanjing University of Aeronautics and Astronautics (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101789
- Citations
- 4
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.07
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
- National Key Research and Development Program of China
- National Key Research and Development Program of China Stem Cell and Translational Research