Adenosine Signaling and Clathrin-Mediated Endocytosis of Glutamate AMPA Receptors in Delayed Hypoxic Injury in Rat Hippocampus: Role of Casein Kinase 2
Autor: | Xin Qin, Elisabet Jakova, Francisco S. Cayabyab, Michael G. Zaki, Zhicheng Chen, Zhi Ming |
---|---|
Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Adenosine Casein kinase 2 Neuroscience (miscellaneous) AMPA receptor Pharmacology Hippocampus Perampanel Neuroprotection Article Ischemic injury Synaptic plasticity Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine Animals Receptors AMPA Adenosine receptors Synaptic transmission Casein Kinase II Hypoxia AMPA receptors Chemistry Glutamate receptor Excitatory Postsynaptic Potentials Long-term potentiation Hypoxia (medical) Adenosine receptor Clathrin Endocytosis Clathrin-mediated endocytosis Rats Dynamin 030104 developmental biology Purinergic P1 Receptor Antagonists nervous system Neurology medicine.symptom 030217 neurology & neurosurgery Signal Transduction medicine.drug |
Zdroj: | Molecular Neurobiology |
ISSN: | 1559-1182 0893-7648 |
DOI: | 10.1007/s12035-020-02246-0 |
Popis: | Chronic adenosine A1R stimulation in hypoxia leads to persistent hippocampal synaptic depression, while unopposed adenosine A2AR receptor stimulation during hypoxia/reperfusion triggers adenosine-induced post-hypoxia synaptic potentiation (APSP) and increased neuronal death. Still, the mechanisms responsible for this adenosine-mediated neuronal damage following hypoxia need to be fully elucidated. We tested the hypothesis that A1R and A2AR regulation by protein kinase casein kinase 2 (CK2) and clathrin-dependent endocytosis of AMPARs both contribute to APSPs and neuronal damage. The APSPs following a 20-min hypoxia recorded from CA1 layer of rat hippocampal slices were abolished by A1R and A2AR antagonists and by broad-spectrum AMPAR antagonists. The inhibitor of GluA2 clathrin-mediated endocytosis Tat-GluA2-3Y peptide and the dynamin-dependent endocytosis inhibitor dynasore both significantly inhibited APSPs. The CK2 antagonist DRB also inhibited APSPs and, like hypoxic treatment, caused opposite regulation of A1R and A2AR surface expression. APSPs were abolished when calcium-permeable AMPAR (CP-AMPAR) antagonist (IEM or philanthotoxin) or non-competitive AMPAR antagonist perampanel was applied 5 min after hypoxia. In contrast, perampanel, but not CP-AMPAR antagonists, abolished APSPs when applied during hypoxia/reperfusion. To test for neuronal viability after hypoxia, propidium iodide staining revealed significant neuroprotection of hippocampal CA1 pyramidal neurons when pretreated with Tat-GluA2-3Y peptide, CK2 inhibitors, dynamin inhibitor, CP-AMPAR antagonists (applied 5 min after hypoxia), and perampanel (either at 5 min hypoxia onset or during APSP). These results suggest that the A1R-CK2-A2AR signaling pathway in hypoxia/reperfusion injury model mediates increased hippocampal synaptic transmission and neuronal damage via calcium-permeable AMPARs that can be targeted by perampanel for neuroprotective stroke therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-020-02246-0. |
Databáze: | OpenAIRE |
Externí odkaz: |