AMPA受体
化学
长时程增强
突触可塑性
神经科学
内吞作用
内化
谷氨酸受体
受体
药理学
生物化学
心理学
生物
作者
Horea Stefan Szedlacsek,Dávid Bajusz,Rodica A. Badea,Andreea Pop,Constantin Cătălin Bică,Lilla Ravasz,Dániel Mittli,Dominik Mátyás,Georgiana Necula-Petrăreanu,Cristian V. A. Munteanu,Ildikó Papp,Gábor Juhász,Lucian Hriţcu,György M. Keserű,Stefan E. Szedlacsek
标识
DOI:10.1021/acs.jmedchem.1c01303
摘要
Cognitive impairment and learning ability of the brain are directly linked to synaptic plasticity as measured in changes of long-term potentiation (LTP) and long-term depression (LTD) in animal models of brain diseases. LTD reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. AMPA receptor endocytosis is initiated by dephosphorylation of Tyr876 on the C-terminus of the AMPAR subunit GluA2. The brain-specific striatal-enriched protein tyrosine phosphatase (STEP) is responsible for this process. To identify new, highly effective inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization, we performed structure-based design of peptides able to inhibit STEP-GluA2-CT complex formation. Two short peptide derivatives were found as efficient in vitro inhibitors. Our in vivo experiments evidenced that both peptides restore the memory deficits and display anxiolytic and antidepressant effects in a scopolamine-treated rat model. The interference peptides identified and characterized here represent promising lead compounds for novel cognitive enhancers and/or behavioral modulators.
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