复旦大学脑科学研究院马兰教授研究团队经3年多研究，最近发现一种在体内广泛存在的蛋白激酶GRK5在神经系统中的功能，以及调节神经元形态和可塑性的新机制，这将给神经元发育异常引起的孤独症和唐氏综合症等疾病的治疗和药物研发提供新的思路。该发现新近刊登在国际著名学术刊物《细胞生物学期刊》上。
神经元又称神经细胞，是构成神经系统结构和功能的基本单位。脑内千千万万个神经元是形成情感、记忆以及意识等脑功能的基础和基本单元。脑神经网络的形成和重塑依赖于神经元的形态生成和动态变化。神经元细胞骨架重构和细胞质膜的变形两者均在神经元形态生成和动态变化中发挥重要作用，但是神经元是如何协调细胞质膜的变形和细胞骨架的重构，从而促进神经突起的生长和神经元之间的联系，一直是难解之谜。
马兰研究组青年研究人员陈跃军、王菲菲、龙慧等通过生物化学、细胞和动物实验得到了一个出人意料的答案：GRK5可以通过另外的方式在神经系统发挥着桥梁的作用，即GRK5的一端可与脑内细胞骨架结合，引起细胞骨架重构，它的另一端可通过结合脑内神经元细胞膜上特异的磷脂“PIP2”，把重构的细胞骨架引导到PIP2富集的细胞质膜区域，从而协调细胞骨架重构和细胞膜的变形，促进神经元的形态变化和神经元之间连接的形成。
陈跃军告诉记者，很多影响认知的疾病，比如孤独症，精神发育迟缓，脆性综合征，唐氏综合征等都伴有神经元形态发育的异常。他们的这一研究发现GRK5具有促进神经元形态发育的新功能，证明GRK5是一个促进神经网络形成、调节脑学习记忆等功能的重要蛋白质，为神经元发育异常引起的精神障碍的治疗和药物研发提供了新靶点。（生物谷 Bioon.com）
doi:10.1083/jcb.201104114
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GRK5 promotes F-actin bundling and targets bundles to membrane structures to control neuronal morphogenesis
Yuejun Chen1,2, Feifei Wang1,2, Hui Long1,2, Ying Chen1,2, Ziyan Wu1,2,
Neuronal morphogenesis requires extensive membrane remodeling and cytoskeleton dynamics. In this paper, we show that GRK5, a G protein–coupled receptor kinase, is critically involved in neurite outgrowth, dendrite branching, and spine morphogenesis through promotion of filopodial protrusion. Interestingly, GRK5 is not acting as a kinase but rather provides a key link between the plasma membrane and the actin cytoskeleton. GRK5 promoted filamentous actin (F-actin) bundling at the membranes of dynamic neuronal structures by interacting with both F-actin and phosphatidylinositol-4,5-bisphosphate. Moreover, separate domains of GRK5 mediated the coupling of actin cytoskeleton dynamics and membrane remodeling and were required for its effects on neuronal morphogenesis. Accordingly, GRK5 knockout mice exhibited immature spine morphology and deficient learning and memory. Our findings identify GRK5 as a critical mediator of dendritic development and suggest that coordinated actin cytoskeleton and membrane remodeling mediated by bifunctional actin-bundling and membrane-targeting molecules, such as GRK5, is crucial for proper neuronal morphogenesis and the establishment of functional neuronal circuitry.
