Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus.
Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus.
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DOI：
10.1073/pnas.98.1.93
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发表时间：
2001-01
影响因子：
11.1
通讯作者：
L. Barak;R. Oakley;S. Laporte;M. G. Caron
中科院分区：
文献类型：
--
作者：
L. Barak;R. Oakley;S. Laporte;M. G. Caron
G蛋白偶联受体的激动剂依赖的脱敏和内化是通过阻滞素与磷酸化受体的结合而介导的。阻滞素对磷酸化的GPCR的亲和力调节内化受体被去磷酸化并循环回到质膜的能力。在这项研究中，我们证明了与家族性肾源性尿崩症相关的自然发生的加压素受体突变R137H功能丧失导致结构性Arrestin介导的脱敏。与野生型加压素受体不同，非信号的R137H受体被磷酸化，即使在没有激动剂的情况下也被隔离在与arrestin相关的细胞内小泡中。消除促进高亲和力arrestin-受体相互作用的受体上的分子决定因素，重建质膜定位和突变受体的信号能力。这些发现表明，非调控脱敏可能导致基于GPCR的疾病的病因学，这意味着GPCR脱敏的药理学靶向可能在治疗上是有益的。
Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestin-mediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin-receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial.