A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration.
A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration.
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DOI：
10.1016/s0021-9258(17)42012-6
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发表时间：
1994-01
期刊：
影响因子：
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通讯作者：
L. Barak;M. Tiberi;N. Freedman;M. Kwatra;R. Lefkowitz;M. G. Caron
中科院分区：
文献类型：
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作者：
L. Barak;M. Tiberi;N. Freedman;M. Kwatra;R. Lefkowitz;M. G. Caron
一个芳香族残基，酪氨酸326在原型的人β 2-肾上腺素能受体，存在于一个高度保守的序列基序，在几乎所有的G蛋白偶联受体家族的成员。通过将酪氨酸残基326替换为丙氨酸残基（β 2AR-Y326 A），评估了这种保守的芳香族氨基酸残基在与激动剂介导的β 2-肾上腺素能受体脱敏相关的螯合（表面受体的快速内化）和下调（总细胞受体的缓慢损失）细胞过程中的潜在作用。该突变完全消除激动剂介导的受体隔离，而不影响受体最大限度地激活腺苷酸环化酶、经历快速脱敏和响应激动剂下调的能力。与突变受体相关的唯一其他主要变化是在快速脱敏后完全丧失再敏感的能力。这些结果意味着，这酪氨酸残基，这是一个高度保守的序列基序的一部分，在G蛋白偶联受体，可能是负责其激动剂介导的隔离和隔离和下调的受体是解离现象。螯合缺陷型β 2-肾上腺素能受体突变体中缺乏再敏化强烈表明，螯合途径是一种重要机制，通过该机制，细胞在去除激动剂后重新建立G蛋白偶联受体的正常反应性。
An aromatic residue, tyrosine 326 in the prototypical human beta 2-adrenergic receptor, exists in a highly conserved sequence motif in virtually all members of the G protein-coupled receptor family. The potential role of this conserved aromatic amino acid residue in the cellular processes of sequestration (a rapid internalization of the surface receptor) and down-regulation (a slower loss of total cellular receptors) associated with agonist-mediated desensitization of the beta 2-adrenergic receptor was assessed by replacing tyrosine residue 326 with an alanine residue (beta 2AR-Y326A). This mutation completely abolishes agonist-mediated receptor sequestration without affecting the ability of the receptor to activate maximally adenylyl cyclase, to undergo rapid desensitization, and to down-regulate in response to agonist. The only other major change associated with the mutated receptor is a complete loss of the ability to resensitize following rapid desensitization. These results imply that this tyrosine residue, which is part of a highly conserved sequence motif in G protein-coupled receptors, may be responsible for their agonist-mediated sequestration and that sequestration and down-regulation of the receptor are dissociable phenomena. The lack of resensitization in the sequestration-defective beta 2-adrenergic receptor mutant strongly suggests that the sequestration pathway is an important mechanism by which cells re-establish the normal responsiveness of G protein-coupled receptors following the removal of agonist.