Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema

Abstract

Background: 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).

Results: 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.

Conclusions: 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.

Keywords: Electrochemistry-tension; Enhanced sensitivity in Na(+)/Cl(-) ion channels; Glutamate receptors co-activation; Neurotoxic edema; Protein nanoparticle-induced osmotic pressure.