CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.
Department of Pharmacology, Vanderbilt University, 2220 Pierce Ave., Preston Research Building 460, Nashville, TN, 37232, USA.
Angew Chem Int Ed Engl. 2024 Dec 2;63(49):e202411181. doi: 10.1002/anie.202411181. Epub 2024 Oct 29.
AMPA receptors (AMPARs) are the main drivers of excitatory glutamatergic transmission in the brain, central to synaptic plasticity, and are key drug targets. However, AMPARs are expressed in virtually every neuron in the central nervous system and are activated with complex temporal dynamics, making it difficult to determine their functional roles with sufficient precision. Here we describe a cell specific, light-controllable competitive antagonist for the AMPA receptor called MP-GluA that combines the temporal precision of a photo-switchable ligand with the spatial and cellular specificity of a genetically-encoded membrane-anchor protein. This tool could pave the way for controlling endogenous AMPARs in neural circuits with cellular, spatial, and temporal specificity.
AMPA 受体（AMPARs）是大脑中兴奋性谷氨酸能传递的主要驱动因素，对突触可塑性至关重要，也是关键的药物靶点。然而，AMPA 受体几乎存在于中枢神经系统的每一个神经元中，并以复杂的时间动态激活，这使得很难精确确定它们的功能作用。在这里，我们描述了一种针对 AMPA 受体的细胞特异性、光可控竞争性拮抗剂，称为 MP-GluA，它结合了光开关配体的时间精度和基因编码的膜锚定蛋白的空间和细胞特异性。该工具可能为以细胞、空间和时间特异性控制神经回路中的内源性 AMPAR 铺平道路。
