1. Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema.
- Author
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Zheng, Zihui, Qiu, Zhaoshun, Xiong, Xiyu, Nie, Aobo, Zhou, Wenzhao, Qiu, Huimin, Zhao, Huanhuan, Wu, Huiwen, and Guo, Jun
- Subjects
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OSMOTIC pressure , *CEREBRAL edema , *ION channels , *MEMBRANE proteins , *MEMBRANE potential - Abstract
Glutamate stimuli and hyperactivation of its receptor are predominant determinants of ischemia-induced cytotoxic cerebral edema, which is closely associated with protein nanoparticle (PN)-induced increases in osmotic pressure. Herein, we investigated the electrochemical and mechanical mechanisms underlying the neuron swelling induced by PNs via the co-activation of N-methyl-D-aspartate receptor subunit (NMDAR) and excitatory metabotropic glutamate receptors (mGluRs). We observed that co-activation of ionic glutamate receptor NMDAR and Group I metabotropic mGluRs promoted alteration of PN-induced membrane potential and increased intracellular osmosis, which was closely associated with calcium and voltage-dependent ion channels. In addition, activation of NMDAR-induced calmodulin (CaM) and mGluR downstream diacylglycerol (DAG)/protein kinase C α (PKCα) were observed to play crucial roles in cytotoxic hyperosmosis. The crosstalk between CaM and PKCα could upregulate the sensitivity and sustained opening of sulfonylurea receptor 1 (SUR1)-transient receptor potential cation channel subfamily M member 4 (TRPM4) and transmembrane protein 16 A (TMEM16A) channels, respectively, maintaining the massive Na+/Cl- influx, and the resultant neuron hyperosmosis and swelling. Intracellular PNs and Na+/Cl- influx were found to be as potential targets for cerebral edema treatment, using the neurocyte osmosis system and a cerebral ischemic rat model. This study highlights PNs as a key factor in "electrochemistry-tension" signal transduction controlling Na+/Cl- ion channels and increased osmotic pressure in ischemia-induced cytotoxic edema. Moreover, enhanced sensitivity in both Na+ and Cl- ion channels also has a crucial role in cerebral edema. [Display omitted] • Co-activation of NMDAR and Group I mGluRs promotes PNs-induced neuronal hyperosmosis. • PNs exert electrophysiological effects and activate ion channels. • PKCα and CaM enhance sensitivity of SUR1-TRPM4 and TMEM16A channel currents. • PNs and Na+ /Cl- influx as potential targets for cerebral edema treatment. • Electrochemistry-tension signal transduction controls cytotoxic cerebral edema. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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