Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by β-adrenergic receptor kinase 1 -: A role in receptor sequestration
Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by β-adrenergic receptor kinase 1 -: A role in receptor sequestration
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DOI：
10.1074/jbc.m102376200
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发表时间：
2001-06-01
影响因子：
4.8
通讯作者：
Rockman, HA
中科院分区：
文献类型：
--
作者：
Prasad, SVN;Barak, LS;Rockman, HA
β-肾上腺素能受体的激动剂依赖性脱敏需要β-肾上腺素能受体激酶1通过释放的G β-γ亚单位的移位和激活。激动剂占据的受体的后续内化是由于β-抑制蛋白与磷酸化受体结合，然后与AP 2衔接子和网格蛋白相互作用而发生的。已知受体内化需要由磷酸肌醇3-激酶作用产生的D-3磷酸肌醇。磷酸肌醇3-激酶形成脂质激酶家族，其通过受体酪氨酸激酶和G蛋白偶联受体偶联信号。磷酸肌醇3-激酶用于促进β-肾上腺素能受体内化的分子机制尚不清楚。在目前的研究中，我们证明了一个新的发现，β-肾上腺素能受体激酶1和磷酸肌醇3-激酶形成胞质复合物，这导致β-肾上腺素能受体激酶1介导的磷酸肌醇3-激酶转运到膜中的激动剂依赖性的方式。此外，激动剂诱导的磷酸肌醇3-激酶易位导致与受体的快速相互作用，这具有功能重要性，因为磷酸肌醇3-激酶活性的抑制减弱了β-肾上腺素能受体螯合。因此，激动剂依赖性的磷酸肌醇3-激酶向膜的募集是受体螯合过程中的重要步骤，并将磷酸肌醇3-激酶与G蛋白偶联受体活化和螯合联系起来。
Agonist-dependent desensitization of the beta -adrenergic receptor requires translocation and activation of the beta -adrenergic receptor kinase1 by liberated G beta gamma subunits. Subsequent internalization of agonist-occupied receptors occurs as a result of the binding of beta -arrestin to the phosphorylated receptor followed by interaction with the AP2 adaptor and clathrin proteins. Receptor internalization is known to require D-3 phosphoinositides that are generated by the action of phosphoinositide 3-kinase. Phosphoinositide 3-kinases form a family of lipid kinases that couple signals via receptor tyrosine kinases and G-protein-coupled receptors, The molecular mechanism by which phosphoinositide 3-kinase acts to promote beta -adrenergic receptor internalization is not well understood. In the present investigation we demonstrate a novel finding that beta -adrenergic receptor kinase 1 and phosphoinositide 3-kinase form a cytosolic complex, which leads to beta -adrenergic receptor kinase 1-mediated translocation of phosphoinositide 3-kinase to the membrane in an agonist-dependent manner. Furthermore, agonist-induced translocation of phosphoinositide 3-kinase results in rapid interaction with the receptor, which is of functional importance, since inhibition of phosphoinositide 3-kinase activity attenuates beta -adrenergic receptor sequestration. Therefore, agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane is an important step in the process of receptor sequestration and links phosphoinositide 3-kinase to G-protein-coupled receptor activation and sequestration.