Design and Characterization of Prodrug-like Inhibitors for Preventing Glutamate Efflux through Reverse Transport

谷氨酸受体 前药 生物化学 化学 流出 细胞外 运输机 生物 谷氨酸 细胞生物学 生物物理学 药理学 氨基酸 基因 受体
作者
Dirk Jan Slotboom,Jiali Wang,Elias Ndaru,Brien Maney,Xiaozhen Yu,Thomas Albers,Christof Grewer
出处
期刊:ACS Chemical Neuroscience [American Chemical Society]
卷期号:14 (23): 4252-4263 被引量:2
标识
DOI:10.1021/acschemneuro.3c00651
摘要

Glutamate transporters are responsible for active transport of the major excitatory neurotransmitter glutamate across the cell membrane, regulating the extracellular glutamate concentration in the mammalian brain. Extracellular glutamate levels in the brain are usually in the submicromolar range but can increase by exocytosis, inhibition of cellular uptake, or through glutamate release by reverse transport, as well as other mechanisms, which can lead to neurodegeneration and neuronal cell death. Such conditions can be encountered upon energy deprivation during an ischemic stroke. Here, we developed acetoxymethyl (AM) ester prodrug-like derivatives of excitatory amino acid transporter (EAAT) inhibitors that permeate the cell membrane and are activated, most likely through hydrolysis by endogenous cellular esterases, to form the active EAAT inhibitor. Upon increase in external K+ concentration, the inhibitors block glutamate efflux by EAAT reverse transport. Using a novel high-affinity fluorescent prodrug-like inhibitor, dl-threo-9-anthracene-methoxy-aspartate (TAOA) AM ester, we demonstrate that the precursor rapidly accumulates inside cells. Electrophysiological methods and fluorescence assays utilizing the iGluSnFR external glutamate sensor were used to demonstrate the efficacy of AM ester-protected inhibitors in inhibiting K+-mediated glutamate release. Together, our results provide evidence for a novel method to potentially prevent glutamate release by reverse transport under pathophysiological conditions in a model cell system, as well as in human astrocytes, while leaving glutamate uptake under physiological conditions operational. This method could have wide-ranging applications in the prevention of glutamate-induced neuronal cell death.
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