Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors.
Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors.
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DOI：
10.3390/pharmaceutics13050636
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发表时间：
2021-04-30
期刊：
影响因子：
5.4
通讯作者：
Jackson DA
中科院分区：
文献类型：
--
作者：
Achzet LM;Astruc-Diaz F;Beske PH;Natale NR;Denton TT;Jackson DA
在美国，中风仍然是导致残疾的主要原因之一。尽管科学界进行了大量的研究，但对中风患者可用的治疗方法很少。细胞内钙离子的细胞毒性堆积是缺血性卒中后发生的一种被广泛研究的现象。这种细胞内钙超载是兴奋性神经递质谷氨酸过度释放的结果，这一过程被称为兴奋性毒性。钙通透性AMPA受体(AMPAR)缺乏GluA2亚单位，导致钙细胞毒性和随后的神经元死亡。缺氧缺糖再灌注(OGD/R)后GluA2 AMPAR亚基的内化和随后的降解至少部分是由蛋白与C激酶1(PICK1)相互作用介导的。本研究的目的是评估PICK1抑制剂FSC231能否阻止OGD/R诱导的GluA2 AMPAR亚单位的降解。利用急性啮齿动物海马片模型系统，我们确定FSC231的预处理阻止了OGD/R诱导的PICK1-GluA2的关联。在OGD/R期间，FSC231治疗挽救了总GluA2 AMPAR亚单位蛋白水平。这表明GluA2和PICK1之间的相互作用在缺血/再灌流引起的总GluA2水平下降中起重要作用。
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.
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影响因子：
--
作者：
FORD, LM;SANBERG, PR;FOGELSON, MH
通讯作者：
FOGELSON, MH
DOI：
10.1074/jbc.m901203200
发表时间：
2009-05-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Dixon RM;Mellor JR;Hanley JG
通讯作者：
Hanley JG
影响因子：
5.3
作者：
Calderone, A;Jover, T;Zukin, RS
通讯作者：
Zukin, RS
影响因子：
2.8
作者：
Falluji, Nezar;Abou-Chebl, Alex;Mukherjee, Debabrata
通讯作者：
Mukherjee, Debabrata
影响因子：
3.2
作者：
Bach A;Stuhr-Hansen N;Thorsen TS;Bork N;Moreira IS;Frydenvang K;Padrah S;Christensen SB;Madsen KL;Weinstein H;Gether U;Strømgaard K
通讯作者：
Strømgaard K