Beta1-adrenergic receptor-mediated dilation of rat cerebral artery requires Shaker-type KV1 channels on PSD95 scaffold.
Beta1-adrenergic receptor-mediated dilation of rat cerebral artery requires Shaker-type KV1 channels on PSD95 scaffold.
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β1-肾上腺素能受体介导的大鼠脑动脉扩张需要 PSD95 支架上的 Shaker 型 KV1 通道。
DOI：
10.1038/jcbfm.2015.91
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Rhee,SungW
中科院分区：
文献类型：
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作者：
Moore,ChristopherL;McClenahan,SamanthaJ;Hanvey,HillaryM;Jang,Dae-Song;Nelson,PiperL;Joseph,BinyK;Rhee,SungW
突触后密度-95(Post Synaptic Density-95，PSD95)是脑血管平滑肌细胞(CVSMCs)中的一种支架蛋白，它与激动型K+(KV1)通道结合，并通过蛋白激酶A的磷酸化促进通道开放。β1肾上腺素能受体(β1ARs)也有PSD95的结合基序。β-1AR通过PSD95与KV1通道的功能联系可能代表了脑动脉(CA)一种新的血管扩张复合体。我们探讨了KV1AR-β-KV1复合体是否是大鼠CA扩张的决定因素。逆转录-聚合酶链式反应和免疫印迹显示β-1AR在CA组织中有表达。异丙肾上腺素对加压大鼠离体颈总动脉具有浓度依赖性的收缩作用，该作用可被β1AR阻断剂CGP20712阻断。大脑中小动脉的颅窗成像显示异丙肾上腺素和去甲肾上腺素诱导的扩张被β1AR阻滞剂钝化。CGP20712可阻断异丙肾上腺素引起的加压CA的cVSMC超极化。β-1AR和PSD95免疫共聚焦图像显示CA裂解液中PSD95与β-1AR免疫共沉淀。阻断KV1通道、阻断β1AR或阻断KV1与KV1的相互作用，与阻断异丙肾上腺素引起的加压CA的扩张作用相似。这些结果表明，PSD95在cVSMCs中与β-1AR和KV1通道介导了一个血管扩张复合体。这种复合体可能是大鼠CA适当扩张血管的关键。
Postsynaptic density-95 (PSD95) is a scaffolding protein in cerebral vascular smooth muscle cells (cVSMCs), which binds toShaker-type K+(KV1) channels and facilitates channel opening through phosphorylation by protein kinase A. β1-Adrenergic receptors (β1ARs) also have a binding motif for PSD95. Functional association of β1AR with KV1 channels through PSD95 may represent a novel vasodilator complex in cerebral arteries (CA). We explored whether a β1AR-PSD95-KV1 complex is a determinant of rat CA dilation. RT-PCR and western blots revealed expression of β1AR in CA. Isoproterenol induced a concentration-dependent dilation of isolated, pressurized rat CA that was blocked by the β1AR blocker CGP20712. Cranial window imaging of middle cerebral arteriolesin situshowed isoproterenol- and norepinephrine-induced dilation that was blunted by β1AR blockade. Isoproterenol-induced hyperpolarization of cVSMCs in pressurized CA was blocked by CGP20712. Confocal images of cVSMCs immunostained with antibodies against β1AR and PSD95 indicated strong colocalization, and PSD95 co-immunoprecipitated with β1AR in CA lysate. Blockade of KV1 channels, β1AR or disruption of PSD95-KV1 interaction produced similar blunting of isoproterenol-induced dilation in pressurized CA. These findings suggest that PSD95 mediates a vasodilator complex with β1AR and KV1 channels in cVSMCs. This complex may be critical for proper vasodilation in rat CA.