title: NMDAR-Mediated Hippocampal Neuronal Death is Exacerbated by Activities of ASIC1a.
abstract: NMDARs and ASIC1a both exist in central synapses and mediate important physiological and pathological conditions, but the functional relationship between them is unclear. Here we report several novel findings that may shed light on the functional relationship between these two ion channels in the excitatory postsynaptic membrane of mouse hippocampus. Firstly, NMDAR activation induced by either NMDA or OGD led to increased [Ca(2+)](i)and greater apoptotic and necrotic cell deaths in cultured hippocampal neurons; these cell deaths were prevented by application of NMDAR antagonists. Secondly, ASIC1a activation induced by pH 6.0 extracellular solution (ECS) showed similar increases in apoptotic and necrotic cell deaths; these cell deaths were prevented by ASIC1a antagonists, and also by NMDAR antagonists. Since increased [Ca(2+)](i)leads to increased cell deaths and since NMDAR exhibits much greater calcium permeability than ASIC1a, these data suggest that ASIC1a-induced neuronal death is mediated through activation of NMDARs. Thirdly, treatment of hippocampal cultures with both NMDA and acidic ECS induced greater degrees of cell deaths than either NMDA or acidic ECS treatment alone. These results suggest that ASIC1a activation up-regulates NMDAR function. Additional data supporting the functional relationship between ASIC1a and NMDAR are found in our electrophysiology experiments in hippocampal slices, where stimulation of ASIC1a induced a marked increase in NMDAR EPSC amplitude, and inhibition of ASIC1a resulted in a decrease in NMDAR EPSC amplitude. In summary, we present evidence that ASIC1a activity facilitates NMDAR function and exacerbates NMDAR-mediated neuronal death in pathological conditions. These findings are invaluable to the search for novel therapeutic targets in the treatment of brain ischemia.
authors.affiliation: Department of Physiology, Binzhou Medical University, Yantai Campus, 346 Guanhai Road, Laishan District, Yantai, 264003, Shandong, China.
authors.forename: Su
authors.initials: S
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Ma
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Zhang
authors.forename: Xing-Tao
authors.initials: XT
authors.lastname: Wang
authors.forename: Chaoyun
authors.initials: C
authors.lastname: Wang
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Fan
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Zheng
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Ma
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology; D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006863:Hydrogen-Ion Concentration; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062687:Sodium Channel Agonists / Q000494:pharmacology; D046509:Tissue Culture Techniques
chemical_list: C568267:ASIC1 protein, mouse; D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D062687:Sodium Channel Agonists; D016202:N-Methylaspartate; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005947:Glucose; D002118:Calcium