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性别依赖性差异在缺血/再灌注诱导的 AMPA 受体表达中。

Sex-Dependent Differences in the Ischemia/Reperfusion-Induced Expression of AMPA Receptors.

机构信息

Department of Pharmaceutical Sciences and Molecular Medicine, Washington State University-Health Sciences, Spokane, WA 99201, USA.

出版信息

Int J Mol Sci. 2024 Feb 13;25(4):2231. doi: 10.3390/ijms25042231.

DOI:10.3390/ijms25042231
PMID:38396906
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10889403/
Abstract

Following ischemia/reperfusion, AMPA receptors (AMPARs) mediate pathologic delayed neuronal death through sustained expression of calcium-permeable AMPARs, leading to excitotoxicity. Preventing the surface removal of GluA2-containing AMPARs may yield new therapeutic targets for the treatment of ischemia/reperfusion. This study utilized acute organotypic hippocampal slices from aged male and female Sprague Dawley rats and subjected them to oxygen-glucose deprivation/reperfusion (OGD/R) to examine the mechanisms underlying the internalization and degradation of GluA2-containing AMPARs. We determined the effect of OGD/R on AMPAR subunits at the protein and mRNA transcript levels utilizing Western blot and RT-qPCR, respectively. Hippocampal slices from male and female rats responded to OGD/R in a paradoxical manner with respect to AMPARs. GluA1 and GluA2 AMPAR subunits were degraded following OGD/R in male rats but were increased in female rats. There was a rapid decrease in GRIA1 (GluA1) and GRIA2 (GluA2) mRNA levels in the male hippocampus following ischemic insult, but this was not observed in females. These data indicate a sex-dependent difference in how AMPARs in the hippocampus respond to ischemic insult, and may help explain, in part, why premenopausal women have a lower incidence/severity of ischemic stroke compared with men of the same age.

摘要

缺血/再灌注后，AMPA 受体（AMPARs）通过持续表达钙通透性 AMPARs 介导病理性延迟性神经元死亡，导致兴奋性毒性。防止 GluA2 包含的 AMPAR 表面去除可能为缺血/再灌注的治疗提供新的治疗靶点。本研究利用雄性和雌性 Sprague Dawley 大鼠的急性器官型海马切片，并对其进行氧葡萄糖剥夺/再灌注（OGD/R），以研究 GluA2 包含的 AMPAR 内化和降解的机制。我们分别利用 Western blot 和 RT-qPCR 确定了 OGD/R 对 AMPAR 亚基在蛋白质和 mRNA 转录水平的影响。雄性和雌性大鼠的海马切片对 OGD/R 的反应表现出一种反常的方式，涉及 AMPARs。在雄性大鼠中，OGD/R 后 GluA1 和 GluA2 AMPAR 亚基被降解，但在雌性大鼠中则增加。缺血性损伤后，雄性海马中的 GRIA1（GluA1）和 GRIA2（GluA2）mRNA 水平迅速下降，但在雌性中未观察到。这些数据表明，海马中的 AMPARs 对缺血性损伤的反应存在性别依赖性差异，这可能部分解释了为什么绝经前女性的缺血性中风发病率/严重程度低于同龄男性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/59c876b4b883/ijms-25-02231-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/35e94420418f/ijms-25-02231-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/21976c412e91/ijms-25-02231-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/afdcb3751152/ijms-25-02231-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/f2edbfc4225f/ijms-25-02231-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/8241b2e56b15/ijms-25-02231-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/7461e5a3ea38/ijms-25-02231-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/4b317136deff/ijms-25-02231-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/06816241e398/ijms-25-02231-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/59c876b4b883/ijms-25-02231-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/35e94420418f/ijms-25-02231-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/21976c412e91/ijms-25-02231-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/afdcb3751152/ijms-25-02231-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/f2edbfc4225f/ijms-25-02231-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/8241b2e56b15/ijms-25-02231-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/7461e5a3ea38/ijms-25-02231-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/4b317136deff/ijms-25-02231-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/06816241e398/ijms-25-02231-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99b6/10889403/59c876b4b883/ijms-25-02231-g009.jpg

相似文献

[1]
Sex-Dependent Differences in the Ischemia/Reperfusion-Induced Expression of AMPA Receptors.

Int J Mol Sci. 2024-2-13

[2]
Oxidative Stress Underlies the Ischemia/Reperfusion-Induced Internalization and Degradation of AMPA Receptors.

Int J Mol Sci. 2021-1-13

[3]
Identification of NADPH oxidase as a key mediator in the post-ischemia-induced sequestration and degradation of the GluA2 AMPA receptor subunit.

J Neurochem. 2015-3

[4]
Endocytosis and lysosomal degradation of GluA2/3 AMPARs in response to oxygen/glucose deprivation in hippocampal but not cortical neurons.

Sci Rep. 2017-9-26

[5]
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J Biol Chem. 2014-1-8

[6]
Protein phosphatase role in adenosine A1 receptor-induced AMPA receptor trafficking and rat hippocampal neuronal damage in hypoxia/reperfusion injury.

Neuropharmacology. 2016-3

[7]
Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation.

Invest Ophthalmol Vis Sci. 2016-2

[8]
Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors.

Pharmaceutics. 2021-4-30

[9]
Prolonged adenosine A1 receptor activation in hypoxia and pial vessel disruption focal cortical ischemia facilitates clathrin-mediated AMPA receptor endocytosis and long-lasting synaptic inhibition in rat hippocampal CA3-CA1 synapses: differential regulation of GluA2 and GluA1 subunits by p38 MAPK and JNK.

J Neurosci. 2014-7-16

[10]
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本文引用的文献

[1]
Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors.

Pharmaceutics. 2021-4-30

[2]
Local translation in neurons: visualization and function.

Nat Struct Mol Biol. 2019-7-3

[3]
Endocytosis and lysosomal degradation of GluA2/3 AMPARs in response to oxygen/glucose deprivation in hippocampal but not cortical neurons.

Sci Rep. 2017-9-26

[4]
Vital Signs: Recent Trends in Stroke Death Rates - United States, 2000-2015.

MMWR Morb Mortal Wkly Rep. 2017-9-8

[5]
NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca²⁺-Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin.

Neuron. 2016-3-2

[6]
Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation.

Invest Ophthalmol Vis Sci. 2016-2

[7]
Identification of NADPH oxidase as a key mediator in the post-ischemia-induced sequestration and degradation of the GluA2 AMPA receptor subunit.

J Neurochem. 2015-3

[8]
Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation.

J Cereb Blood Flow Metab. 2014-12

[9]
Subunit-specific trafficking mechanisms regulating the synaptic expression of Ca(2+)-permeable AMPA receptors.

Semin Cell Dev Biol. 2013-12-15

[10]
The balance between receptor recycling and trafficking toward lysosomes determines synaptic strength during long-term depression.

J Neurosci. 2012-9-19

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