Beta-adrenergic receptor sequestration. A potential mechanism of receptor resensitization.
Beta-adrenergic receptor sequestration. A potential mechanism of receptor resensitization.
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DOI：
10.1016/s0021-9258(18)54155-7
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发表时间：
1993-01
期刊：
影响因子：
--
通讯作者：
Steven Yu;R. Lefkowitz;W. Hausdorff
中科院分区：
文献类型：
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作者：
Steven Yu;R. Lefkowitz;W. Hausdorff
细胞连续暴露于激素激动剂通常会导致刺激反应的快速减弱。这种脱敏作用在β-肾上腺素能受体系统中得到了广泛的研究，主要归因于两种激酶对受体的快速磷酸化。在类似的时间范围内（秒到分钟），激动剂也会触发受体结合亲水性而非疏水性配体的能力的选择性丧失，这种现象称为螯合。有一些证据表明，隔离代表了受体的快速内化，但隔离的功能意义仍不清楚。在去除激动剂后，脱敏和隔离都很容易逆转，具有相似的动力学（t1/2约为3分钟）。为了研究受体螯合参与腺苷酸环化酶反应再敏感的可能性，我们采用了两种不同的方法来阻断受体螯合：用蔗糖预处理细胞和通过位点特异性诱变产生螯合缺陷的β 2-肾上腺素能受体。这两种方法都有效地禁用受体螯合，对腺苷酸环化酶刺激或脱敏的影响很小。然而，在这两种情况下，没有恢复从脱敏是明显的，即使20分钟后，激动剂去除。同样，用伴刀豆球蛋白A预处理细胞几乎完全阻断受体螯合和再敏化，但仅部分抑制其他受体功能。因此，我们的研究结果表明，螯合β 2-肾上腺素能受体是一种机制，涉及重新激活和回收脱敏受体。
Continuous exposure of cells to hormonal agonists often causes a rapid waning of the stimulated response. This desensitization effect has been extensively studied in the beta-adrenergic receptor system, and attributed largely to the rapid phosphorylation of the receptor by two kinases. Over a similar time frame (seconds to minutes), agonists also trigger a selective loss in the capacity of receptors to bind hydrophilic but not hydrophobic ligands, a phenomenon termed sequestration. There is some evidence suggesting that sequestration represents the rapid internalization of receptors, but the functional significance of sequestration has remained unclear. Upon the removal of agonist, both desensitization and sequestration are readily reversed with similar kinetics (t1/2 approximately 3 min for both). To investigate the possibility that receptor sequestration is involved in this resensitization of the adenylyl cyclase response, we applied two distinct approaches to block receptor sequestration: by pretreating cells with sucrose and by creating a sequestration-defective beta 2-adrenergic receptor by site-specific mutagenesis. Both approaches effectively disabled receptor sequestration, with little effect on adenylyl cyclase stimulation or on desensitization. However, in both cases, no recovery from desensitization was apparent even 20 min after the removal of agonist. Similarly, pretreating cells with concanavalin A almost completely blocked receptor sequestration and resensitization but only partially inhibited other receptor functions. Our results therefore suggest that sequestration of beta 2-adrenergic receptors is a mechanism involved in reactivating and recycling desensitized receptors.