Bouvier M, Hausdorff W P, De Blasi A, O'Dowd B F, Kobilka B K, Caron M G, Lefkowitz R J
Howard Hughes Medical Institute Laboratories, Department of Physiology, Duke University Medical Center, Durham, North Carolina 27710.
Nature. 1988 May 26;333(6171):370-3. doi: 10.1038/333370a0.
Eukaryotic cells have evolved a variety of mechanisms for dampening their responsiveness to hormonal stimulation in the face of sustained activation. The mechanisms for such processes, collectively referred to as desensitization, often involve alterations in the properties and number of cell-surface hormone receptors. It has been speculated that phosphorylation-dephosphorylation reactions, which are known to regulate the catalytic activities of enzymes, also regulate the function of receptors. Highly specific receptor kinases, such as rhodopsin kinase and beta-adrenergic receptor kinase, which show stimulus-dependent phosphorylation of receptors have been described. Direct evidence for a causal relationship between receptor phosphorylation and desensitization has been lacking however. Here we report that prevention of agonist-stimulated beta 2-adrenergic receptor (beta 2AR) phosphorylation by truncation of its serine and threonine-rich phosphate acceptor segment delays the onset of desensitization. We also show that selective replacement of these serine and threonine residues by alanine and glycine delays desensitization even further. These data provide the first direct evidence that one molecular mechanism of desensitization of G-protein-coupled receptors involves their agonist-induced phosphorylation.
面对持续激活，真核细胞已进化出多种机制来减弱其对激素刺激的反应性。这些过程的机制统称为脱敏，通常涉及细胞表面激素受体的性质和数量的改变。据推测，已知可调节酶催化活性的磷酸化-去磷酸化反应也调节受体的功能。已经描述了高度特异性的受体激酶，如视紫红质激酶和β-肾上腺素能受体激酶，它们显示出受体的刺激依赖性磷酸化。然而，受体磷酸化与脱敏之间因果关系的直接证据一直缺乏。在这里，我们报告通过截断富含丝氨酸和苏氨酸的磷酸受体片段来防止激动剂刺激的β2-肾上腺素能受体（β2AR）磷酸化会延迟脱敏的开始。我们还表明，用丙氨酸和甘氨酸选择性取代这些丝氨酸和苏氨酸残基会进一步延迟脱敏。这些数据提供了第一个直接证据，即G蛋白偶联受体脱敏的一种分子机制涉及其激动剂诱导的磷酸化。
