復(fù)旦大學(xué)腦科學(xué)研究院馬蘭教授研究團(tuán)隊(duì)經(jīng)3年多研究,，最近發(fā)現(xiàn)一種在體內(nèi)廣泛存在的蛋白激酶GRK5在神經(jīng)系統(tǒng)中的功能,，以及調(diào)節(jié)神經(jīng)元形態(tài)和可塑性的新機(jī)制,，這將給神經(jīng)元發(fā)育異常引起的孤獨(dú)癥和唐氏綜合癥等疾病的治療和藥物研發(fā)提供新的思路,。該發(fā)現(xiàn)新近刊登在國(guó)際著名學(xué)術(shù)刊物《細(xì)胞生物學(xué)期刊》上,。
神經(jīng)元又稱神經(jīng)細(xì)胞,，是構(gòu)成神經(jīng)系統(tǒng)結(jié)構(gòu)和功能的基本單位,。腦內(nèi)千千萬萬個(gè)神經(jīng)元是形成情感,、記憶以及意識(shí)等腦功能的基礎(chǔ)和基本單元。腦神經(jīng)網(wǎng)絡(luò)的形成和重塑依賴于神經(jīng)元的形態(tài)生成和動(dòng)態(tài)變化,。神經(jīng)元細(xì)胞骨架重構(gòu)和細(xì)胞質(zhì)膜的變形兩者均在神經(jīng)元形態(tài)生成和動(dòng)態(tài)變化中發(fā)揮重要作用,，但是神經(jīng)元是如何協(xié)調(diào)細(xì)胞質(zhì)膜的變形和細(xì)胞骨架的重構(gòu)，從而促進(jìn)神經(jīng)突起的生長(zhǎng)和神經(jīng)元之間的聯(lián)系,，一直是難解之謎,。
馬蘭研究組青年研究人員陳躍軍,、王菲菲、龍慧等通過生物化學(xué),、細(xì)胞和動(dòng)物實(shí)驗(yàn)得到了一個(gè)出人意料的答案：GRK5可以通過另外的方式在神經(jīng)系統(tǒng)發(fā)揮著橋梁的作用,，即GRK5的一端可與腦內(nèi)細(xì)胞骨架結(jié)合，引起細(xì)胞骨架重構(gòu),，它的另一端可通過結(jié)合腦內(nèi)神經(jīng)元細(xì)胞膜上特異的磷脂“PIP2”,，把重構(gòu)的細(xì)胞骨架引導(dǎo)到PIP2富集的細(xì)胞質(zhì)膜區(qū)域，從而協(xié)調(diào)細(xì)胞骨架重構(gòu)和細(xì)胞膜的變形,，促進(jìn)神經(jīng)元的形態(tài)變化和神經(jīng)元之間連接的形成,。
陳躍軍告訴記者，很多影響認(rèn)知的疾病,，比如孤獨(dú)癥,，精神發(fā)育遲緩，脆性綜合征,，唐氏綜合征等都伴有神經(jīng)元形態(tài)發(fā)育的異常,。他們的這一研究發(fā)現(xiàn)GRK5具有促進(jìn)神經(jīng)元形態(tài)發(fā)育的新功能，證明GRK5是一個(gè)促進(jìn)神經(jīng)網(wǎng)絡(luò)形成,、調(diào)節(jié)腦學(xué)習(xí)記憶等功能的重要蛋白質(zhì),，為神經(jīng)元發(fā)育異常引起的精神障礙的治療和藥物研發(fā)提供了新靶點(diǎn)。（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.
