Relationship between internalization and mRNA decay in down-regulation of recombinant type 1 angiotensin II receptor (AT1) expression in smooth muscle cells
Relationship between internalization and mRNA decay in down-regulation of recombinant type 1 angiotensin II receptor (AT1) expression in smooth muscle cells
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DOI：
10.1124/mol.55.6.1028
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发表时间：
1999-06-01
影响因子：
3.6
通讯作者：
Murphy, TJ
中科院分区：
文献类型：
--
作者：
Adams, B;Obertone, TS;Murphy, TJ
在血管平滑肌细胞中，激素血管紧张素II被认为引起7 -跨膜结构域1型血管紧张素II受体（AT(1)-R）的内化，但它也抑制受体mRNA的表达。对于该基因超家族中类似调控的成员，这些过程在受体下调中的相对作用尚不清楚。在本研究中，利用逆转录病毒载体系统从四环素抑制启动子合成重组AT(1)-R mRNA于A7r5血管平滑肌细胞。血管紧张素II诱导细胞表面AT(1)-R蛋白的深度内化，但对稳态AT(1)-R mRNA水平没有影响。在大剂量或长时间给药血管紧张素II后不久，细胞表面AT(1)-R表达恢复，表明存在一个重要的恢复性外化途径。当重组AT(1)-R基因的转录被无水四环素共处理的细胞抑制时，这种恢复的程度明显减弱。虽然激动剂刺激的内化似乎直接导致AT(1)-R蛋白的缺失，但这些观察结果提供了直接证据，表明AT(1)-R mRNA含量的降低在持续的AT(1)-R下调中起着重要作用。
In vascular smooth muscle cells, the hormone angiotensin II is thought to cause internalization of the seven-transmembrane domain type 1 angiotensin II receptor (AT(1)-R) but it also suppresses expression of the receptor mRNA. As for similarly regulated members of this gene superfamily, the relative roles of these processes in receptor down-regulation are not well understood. In this study a recombinant AT(1)-R mRNA was synthesized in A7r5 vascular smooth muscle cells from a tetracycline suppressible promoter using a retroviral vector system. Angiotensin II induces a profound internalization of the cell surface AT(1)-R protein but has no effect on steady-state AT(1)-R mRNA levels. Shortly after either bolus or prolonged dosing with angiotensin II, cell surface AT(1)-R expression recovers, indicating the existence of a significant restorative externalization pathway. The extent of this recovery is attenuated markedly when transcription of the recombinant AT(1)-R gene is suppressed by cotreatment of the cells with anhydrotetracycline. Although agonist-stimulated internalization appears to contribute directly to a loss of AT(1)-R protein, these observations provide direct evidence that a reduction in AT(1)-R mRNA content plays a significant role in sustained AT(1)-R down-regulation.