去甲肾上腺素激活星形胶质细胞内核膜上的β1-肾上腺素能受体  

Norepinephrine activatesβ1-adrenergic receptors at the inner nuclear membrane in astrocytes

作　　者：Kelsey C Benton Daniel S Wheeler Beliz Kurtoglu Mahshid Bagher Zadeh Ansari Daniel P Cibich Dante A Gonzalez Matthew R Herbst Saema Khursheed Rachel C Knorr Doug Lobner Jenree G Maglasang Kayla E Rohr Analisa Taylor Robert C Twining Paul JWitt Paul J Gasser 杜一星(编译) 

机构地区：[1]Department of Biomedical Sciences,Marquette University,Milwaukee,Wisconsin,USA [2]不详

出　　处：《神经损伤与功能重建》2022年第7期434-434,共1页Neural Injury and Functional Reconstruction

摘　　要：去甲肾上腺素对星形胶质细胞的代谢、神经保护和免疫调节功能有强大的影响。直到最近,去甲肾上腺素的所有作用尚被认为是由仅存在于细胞质膜的受体介导的。然而,最近对心肌细胞的研究已经确定定位于细胞内膜(包括高尔基体和内核膜)的肾上腺素能受体,并表明去甲肾上腺素可以通过转运蛋白介导的摄取而作用于这些受体。我们最近发现了一种高容量去甲肾上腺素转运蛋白有机阳离子转运蛋白3(OCT3)。该转运蛋白密集定位于星形胶质细胞的外核膜,这表明肾上腺素能信号传导也可能发生在这些细胞的内核膜上。本研究证实:使用免疫荧光和蛋白质印迹技术显示β1-肾上腺素受体定位于星形胶质细胞内核膜;关键的肾上腺素能信号通路组分存在于星形胶质细胞核中;且OCT3和其他儿茶酚胺转运蛋白于星形胶质细胞质膜和核膜均表达。为了测试核膜β1-肾上腺素能受体的功能,我们使用荧光生物传感器实时监测星形胶质细胞核中的蛋白激酶A(PKA)活性。用去甲肾上腺素处理星形胶质细胞会导致核区室中PKA活性的快速增加。用儿茶酚胺摄取抑制剂预处理星形胶质细胞可阻断去甲肾上腺素诱导的核PKA活性的快速增加。这些研究首次记录了任何中枢神经系统细胞核膜上的功能性肾上腺素能受体,揭示了去甲肾上腺素可能直接影响核过程的新机制。这种机制可能与先前描述的去甲肾上腺素的神经保护、代谢和免疫调节作用有关。Norepinephrine exerts powerful influences on the metabolic,neuroprotective and immunoregulatory func-tions of astrocytes.Until recently,all effects of norepinephrine were believed to be mediated by receptors localized ex-clusively to the plasma membrane.However,recent studies in cardiomyocytes have identified adrenergic receptors lo-calized to intracellular membranes,including Golgi and inner nuclear membranes,and have shown that norepineph-rine can access these receptors via transporter-mediated uptake.We recently identified a high-capacity norepinephrine transporter,organic cation transporter 3(OCT3),densely localized to outer nuclear membranes in astrocytes,suggest-ing that adrenergic signaling may also occur at the inner nuclear membrane in these cells.Here,we used immunofluo-rescence and western blot to show thatβ1-adrenergic receptors are localized to astrocyte inner nuclear membranes;that key adrenergic signaling partners are present in astrocyte nuclei;and that OCT3 and other catecholamine transport-ers are localized to astrocyte plasma and nuclear membranes.To test the functionality of nuclear membraneβ1-adrener-gic receptors,we monitored real-time protein kinase A(PKA)activity in astrocyte nuclei using a fluorescent biosensor.Treatment of astrocytes with norepinephrine induced rapid increases in PKA activity in the nuclear compartment.Pre-treatment of astrocytes with inhibitors of catecholamine uptake blocked rapid norepinephrine-induced increases in nu-clear PKA activity.These studies,the first to document functional adrenergic receptors at the nuclear membrane in any central nervous system cell,reveal a novel mechanism by which norepinephrine may directly influence nuclear pro-cesses.This mechanism may contribute to previously described neuroprotective,metabolic and immunoregulatory ac-tions of norepinephrine.

关 键 词：G蛋白偶联受体 肾上腺素受体 单胺转运体 去甲肾上腺素 细胞核 蛋白激酶A 亚细胞定位 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]