Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion.
Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion.
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DOI：
10.1089/neu.2018.5986
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发表时间：
2019-04-01
影响因子：
4.2
通讯作者：
Simard JM
中科院分区：
文献类型：
--
作者：
Gerzanich V;Stokum JA;Ivanova S;Woo SK;Tsymbalyuk O;Sharma A;Akkentli F;Imran Z;Aarabi B;Sahuquillo J;Simard JM
在严重创伤性脑损伤（TBI）中，挫伤通常会因挫伤扩大或挫伤出血进展（HPC）而恶化，这可能使原始挫伤体积加倍并使结局恶化。在人类和啮齿类动物挫伤-TBI中，磺酰脲受体1（SUR 1）在微血管和星形胶质细胞中上调，在啮齿类动物模型中，格列本脲阻断SUR 1可降低HPC。SUR 1本身不起作用，但必须与KIR6.2或瞬时受体电位阳离子通道亚家族M成员4（TRPM 4）共组装以形成KATP（SUR 1-KIR6.2）或SUR 1-TRPM 4通道，两者对膜电位具有相反的作用。据报道，KIR6.2和TRPM 4在TBI中上调，特别是在星形胶质细胞中，但TBI后SUR 1调节通道的身份和功能尚不清楚。在这里，我们分析了人类和大鼠脑组织挫伤后TBI的特点SUR 1，TRPM 4，和KIR6.2的表达，并在大鼠模型中，检查HPC的抑制表达的三个亚基使用静脉内反义寡核苷酸（AS-ODN）的影响。胶质细胞酸性蛋白（GFAP）的免疫反应性被用来操作定义核心与半暗带组织。在人类和大鼠中，GFAP阴性核心组织含有表达SUR 1和TRPM 4的微血管，而GFAP阳性半暗带组织含有表达所有三种亚基的星形胶质细胞。Förster共振能量转移成像显示SUR 1-TRPM 4异聚体存在于内皮细胞，SUR 1-TRPM 4和SUR 1-KIR6.2异聚体存在于星形胶质细胞。在大鼠中，格列本脲以及靶向SUR 1和TRPM 4而非KIR6.2的AS-ODN在TBI后24小时降低HPC。我们的研究结果证实了挫伤-TBI后SUR 1-TRPM 4和KATP的上调，确定SUR 1-TRPM 4是导致HPC的主要分子机制，并表明SUR 1-TRPM 4是格列本脲的关键靶点。
In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form KATP (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and KATP after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide.
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影响因子：
2.9
作者：
Dunn-Meynell, AA;Rawson, NE;Levin, BE
通讯作者：
Levin, BE
影响因子：
6.4
作者：
GRAHAM, DI;ADAMS, JH;GENNARELLI, TA
通讯作者：
GENNARELLI, TA
影响因子：
4.2
作者：
DIETRICH, WD;ALONSO, O;HALLEY, M
通讯作者：
HALLEY, M
影响因子：
5.3
作者：
Chen, MK;Simard, JM
通讯作者：
Simard, JM
影响因子：
4
作者：
Cheng, Henrique;Beck, Andreas;Penner, Reinhold
通讯作者：
Penner, Reinhold