A mechanistic role for polypeptide hormone receptor lateral mobility in signal transduction
A mechanistic role for polypeptide hormone receptor lateral mobility in signal transduction
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DOI：
10.1007/bf00805831
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发表时间：
1995-06
期刊：
影响因子：
3.5
通讯作者：
D. A. Jans;I. Pávó
中科院分区：
文献类型：
--
作者：
D. A. Jans;I. Pávó
膜整合受体在膜平面内的侧向扩散被认为是信号转导的重要机制。使用荧光光漂白恢复技术直接测量多肽激素受体的横向流动性表明，酪氨酸激酶受体在生理温度下基本上是不动的。这可能是由于它们的信号转导机制，其需要通过受体二聚化的分子间自磷酸化，从而固定化以活化。相比之下，G蛋白偶联受体必须与其他膜组分相互作用以实现信号转导，与此一致，磷脂酶C激活加压素V1和腺苷酸环化酶激活V2受体在37°C下高度横向移动的。V2受体移动的部分（f）的调节已证明在37°C下f与受体激动剂依赖性最大cAMP产生之间存在直接相关性。这表明f是激素信号转导中的关键参数，特别是在生理激素浓度下，与实现G蛋白的V2激动剂依赖性活化所需的移动的受体一致。使用V2特异性拮抗剂的测量显示，拮抗剂占据的受体在37°C下是高度移动的，表明受体固定不是拮抗作用的基础。然而，与激动剂占据的受体相反，拮抗剂占据的受体在内吞和下调之前不被固定。因此，受体可以在没有激动性配体的情况下自由移动的;激素激动剂的刺激导致受体与其他蛋白质（可能包括细胞骨架组分）结合并固定。受体固定可能是激动刺激后脱敏的重要步骤之一，通过终止受体侧向运动，有助于在膜平面内产生和放大初始刺激信号。
Lateral diffusion of membrane-integral receptors within the plane of the membrane has been postulated to be mechanistically important for signal transduction. Direct measurement of polypeptide hormone receptor lateral mobility using fluorescence photobleaching recovery techniques indicates that tyrosine kinase receptors are largely immobile at physiological temperatures. This is presumably due to their signal transduction mechanism which requires intermolecular autophosphorylation through receptor dimerization and thus immobilization for activation. In contrast, G-protein coupled receptors must interact with other membrane components to effect signal transduction, and consistent with this, the phospholipase C-activating vasopressin V1- and adenylate cyclase activating V2-receptors are highly laterally mobile at 37°C. Modulation of the V2-receptor mobile fraction (f) has demonstrated a direct correlation between f and receptor-agonist-dependent maximal cAMP productionin vivoat 37°C. This indicates that f is a key parameter in hormone signal transduction especially at physiological hormone concentrations, consistent with mobile receptors being required to effect V2-agonist-dependent activation of G-proteins. Measurements using a V2-specific antagonist show that antagonist-occupied receptors are highly mobile at 37°C, indicating that receptor immobilization is not the basis of antagonism. In contrast to agonist-occupied receptor however, antagonistoccupied receptors are not immobilized prior to endocytosis and down-regulation. Receptors may thus be freely mobile in the absence of agonistic ligand; stimulation by hormone agonist results in receptor association with other proteins, probably including cytoskeletal components, and immobilization. Receptor immobilization may be one of the important steps of desensitization subsequent to agonistic stimulation, through terminating receptor lateral movement which is instrumental in generating and amplifying the initial stimulatory signal within the plane of the membrane.