一项新的有关受体信号的研究将可能带来更好的药物设计方法。美国全国儿童医院的这项研究表明，蛋白质α-arrestin可能在细胞信号传递中发挥着重要的作用。细胞信号传递对于新药研发是非常关键的因素。这项研究发表在PLOS ONE杂志上。
市面上大约有三分之一以上的药物是通过靶定G蛋白偶联受体来起作用的，G蛋白偶联受体控制和细胞交流和其作用的方式。G蛋白偶联受体有好几百种，是人体内最大的信号受体家族。
一旦细胞的G蛋白偶联受体与天然配体或药物结合，细胞内的G蛋白和β-arrestin就会独立介导各种信号。随即，β-arrestin阻断G蛋白的进一步信号传递并“召集”蛋白质移除受体，从而阻止细胞信号。那些受体随后可回收到细胞表面或被摧毁。
“由β-arrestin导致的受体下调会干扰药物的效果，因为药物需要靶定的G蛋白偶联受体不在细胞的表面了，”该研究的主要作者Carlos E. Alvarez博士说。“这也是为什么一些患者在长期服药后产生抗药性，对剂量的需求越来越高。”
在某些情况下，药物触发β-arrestin效果并阻断G蛋白信号传导的作用则正是所需要的。例如β阻断剂，正如其名称所表达的，β阻断剂干扰肾上腺素以及其他经济急速与受体的结合，削弱激素的效果。这种作用可用于治疗心律不齐、防止心脏病二次发作、高血压以及其他病状。筛选试验表明，β阻断剂Carvedilol可能是最理想的心脏病治疗药物，因为它在降低G蛋白信号传递导致的对心脏不利效果的同时，也增强了β-arrestin信号传递对心脏的保护作用。
然而，β-arrestin似乎只与细胞信号传递有关。在2008年，Alvarez博士发现了arrestin的一个亚族并命名为α-arrestin。在最新的研究中，Alvarez博士实验室的Fortune Shea利用生物化学和成像技术对α-arrestin在细胞信号传递中的作用进行了进一步的确定。
他发现，α-arrestin能够对受体结合作出响应并“召集”对受体进行化学修饰的酶类从而启动下调。这些效果发生在受体结合后的前5分钟。在这个时间段，β-arrestin也在触发下调中起到了作用。该研究团队也是首次发现α-arrestin与β-arrestin协同作用。
“我们的研究表明，α-arrestin就像β-arrestin一样，是普遍存在的G蛋白偶联受体信号传递的调节因子，”Alvarez博士说，“α-arrestin似乎和β-arrestin一样具有巨大的药理相关性。”
Alvarez认为α-arrestin将在药物研发中发挥重要作用。“我相信，以α-arrestin为靶标可以让我们开发出更加高效、副作用更少的药物。”
Mammalian Alpha Arrestins Link Activated Seven Transmembrane Receptors to Nedd4 Family E3 Ubiquitin Ligases and Interact with Beta Arrestins
Fortune F. Shea et al.
The complement of fungal cell surface proteins is widely regulated by ubiquitination of membrane proteins, which results in their endocytosis and vacuolar degradation. For diverse fungal transporters, the specificity of ubiquitination is conferred by alpha arrestin adaptors, which recruit the Nedd4 family E3 ubiquitin ligase Rsp5. A recent study showed that one mammalian alpha arrestin also mediates ubiquitination and lysosomal trafficking of an activated plasma membrane receptor. Here we first screen all five widely-expressed human alpha arrestins for subcellular localization in ligand-stimulated and -unstimulated cells overexpressing the seven transmembrane receptor vasopressin 2. We then characterize the effects of alpha arrestins ARRDC3 and ARRDC4 upon activation of the seven transmembrane receptors vasopressin 2 and beta adrenergic 2. Using biochemical and imaging approaches, we show that ligand-activated receptors interact with alpha arrestins, and this results in recruitment of Nedd4 family E3 ubiquitin ligases and receptor ubiquitination – which are known to result in lysosomal trafficking. Our time course studies show these effects occur in the first 1–5 minutes after ligand activation, the same time that beta arrestins are known to have roles in receptor endocytic trafficking and kinase signaling. We tested the possibility that alpha and beta arrestins function coordinately and found co-immunoprecipitation and colocalization evidence to support this. Others recently reported that Arrdc3 knockout mice are lean and resistant to obesity. In the course of breeding our own Arrdc3-deficient mice, we observed two novel phenotypes in homozygotes: skin abnormalities, and embryonic lethality on normal chow diet, but not on high fat diet. Our findings suggest that alpha and beta arrestins function coordinately to maintain the optimal complement and function of cell surface proteins according to cellular physiological context and external signals. We discuss the implications of the alpha arrestin functions in fungi having evolved into coordinated alpha/beta arrestin functions in animals.
