Achzet Lindsay M, Astruc-Diaz Fanny, Beske Phillip H, Natale Nicholas R, Denton Travis T, Jackson Darrell A
Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99202, USA.
Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, USA.
Pharmaceutics. 2021 Apr 30;13(5):636. doi: 10.3390/pharmaceutics13050636.
Strokes remain one of the leading causes of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity. Calcium-permeable AMPA receptors (AMPARs), lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C kinase-1 (PICK1). The purpose of the present study is to evaluate whether treatment with a PICK1 inhibitor, FSC231, prevents the OGD/R-induced degradation of the GluA2 AMPAR subunit. Utilizing an acute rodent hippocampal slice model system, we determined that pretreatment with FSC231 prevented the OGD/R-induced association of PICK1-GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This suggests that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels.
中风仍然是美国导致残疾的主要原因之一。尽管科学界投入了大量研究精力，但针对中风患者的治疗方法却非常有限。细胞内钙的细胞毒性积累是缺血性中风后一种经过充分研究的现象。这种细胞内钙超载是由兴奋性神经递质谷氨酸的过度释放引起的，这一过程称为兴奋性毒性。缺乏GluA2亚基的钙通透性AMPA受体（AMPARs）会导致钙细胞毒性及随后的神经元死亡。氧糖剥夺/再灌注（OGD/R）后GluA2 AMPAR亚基的内化及随后的降解至少部分是由与C激酶-1相互作用的蛋白（PICK1）介导的。本研究的目的是评估PICK1抑制剂FSC231的治疗是否能防止OGD/R诱导的GluA2 AMPAR亚基降解。利用急性啮齿动物海马切片模型系统，我们确定用FSC231预处理可防止OGD/R诱导的PICK1与GluA2的结合。在OGD/R期间用FSC231治疗可挽救GluA2 AMPAR亚基的总蛋白水平。这表明GluA2与PICK1之间的相互作用是缺血/再灌注诱导的GluA2总水平降低的重要步骤。
