天然平滑肌细胞α - 1肾上腺素受体细胞定位的药理意义

J. C. McGrath, J. F. Mackenzie, C. J. Daly
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引用次数: 25

摘要

本研究考察了α - 1肾上腺素能受体的细胞定位,并证明了与天然平滑肌细胞内受体结合位点的结合可能影响激动剂或拮抗剂的药理学特征。研究样本组织为大鼠基底动脉。作为α - 1肾上腺素受体拮抗剂和prazosin的荧光类似物,BODIPY-FL prazosin (QAPB)可以在活的天然细胞上以高分辨率显示质膜和细胞质结合位点,正如之前在含有重组受体的细胞中所显示的那样。qapb相关的荧光结合在大鼠基底平滑肌细胞中具有时间和浓度依赖性,根据特异性结合曲线计算α1-肾上腺素受体的亲和力为1.1 nM。3从大鼠基底动脉分离的平滑肌细胞中检测到的QAPB的浓度依赖性结合由弥漫性和聚集性荧光组成。在QAPB浓度为5 nM时,荧光的漫射成分更为明显。通过细胞的光学切片共聚焦显示,聚集成分主要位于细胞内。在大鼠基底动脉平滑肌细胞中,细胞内结合位点靠近核膜。4 qapb相关荧光的3D模型表明,很大比例的有效结合位点在细胞内,这表明不仅有很大比例的受体位于细胞内,而且在这个位置它们可以结合配体。这对……与细胞内结合本身的后果有关的药理学分析,以及根据它们是否能进入细胞而对特定配体的药理学产生的不同影响。
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Pharmacological implications of cellular localization of α1-adrenoceptors in native smooth muscle cells

1 This study examines the cellular localization of α1-adrenoceptors and demonstrates that binding to intracellular receptive binding sites in native smooth muscle cells may influence the pharmacological profile of agonists or antagonists. The example tissue studied was rat basilar artery.

2 An α1-adrenoceptor antagonist and fluorescent analogue of prazosin, BODIPY-FL prazosin (QAPB) allowed visualization, with high resolution, of both plasma membrane and cytosolic binding sites on live native cells, as previously shown in cells harbouring recombinant receptors. QAPB-associated fluorescence binding was both time- and concentration- dependent in rat basilar smooth muscle cells and affinity for α1-adrenoceptors was calculated from specific binding curves as 1.1 nM.

3 Concentration-dependent binding of QAPB detected in smooth muscle cells dissociated from rat basilar arteries was composed of diffuse and clustered fluorescence. Visually the diffuse component of fluorescence was the more evident up to a concentration of 5 nM QAPB. Confocal visualization of an optical section through the cell showed that the clustered component was located mainly intracellularly. In rat basilar artery smooth muscle cells the intracellular binding sites were located in close proximity to the nuclear membrane.

4 3D models of QAPB-associated fluorescence demonstrate that a high proportion of effective binding sites are intracellular, showing not only that a high proportion of receptors are located inside the cell but also that in this location they can bind ligands. This has implications for. pharmacological analysis in relation to the consequences of intracellular binding per se and for differential effects upon the pharmacology of particular ligands according to whether they can enter the cell.

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