2012年8月13日 訊 /生物谷BIOON/ --星形膠質(zhì)細(xì)胞(astrocyte)之前被認(rèn)為是神經(jīng)元的輔助性細(xì)胞，如今研究人員發(fā)現(xiàn)它們自己能夠給發(fā)送化學(xué)信號(hào)而不是電信號(hào),。它們將這些化學(xué)信號(hào)發(fā)送給神經(jīng)元,、血管細(xì)胞和其他星形膠質(zhì)細(xì)胞來改善突觸信號(hào)傳送效率。日本理化研究所腦科學(xué)研究院研究員Katsuhiko Mikoshiba和Hiroko Bannai領(lǐng)導(dǎo)的一個(gè)研究小組描述了允許星形膠質(zhì)細(xì)胞給它們網(wǎng)絡(luò)中的每個(gè)細(xì)胞發(fā)送信號(hào)的機(jī)制,。
星形膠質(zhì)細(xì)胞擁有一個(gè)位于中間的胞體(soma)和許多個(gè)射線狀臂(ray-like arm),，而且這些射線狀臂連接到它們調(diào)節(jié)的細(xì)胞上。健康的星形膠質(zhì)細(xì)胞通過每個(gè)射線狀臂發(fā)送相互獨(dú)立的鈣離子信號(hào),。已知這些信號(hào)受到細(xì)胞膜中一種被稱作代謝型谷氨酸受體(metabotropic glutamate receptor, mGluR5)的受體的調(diào)節(jié),，但是科學(xué)家們不清楚的是如何將這些信號(hào)分解為單個(gè)鈣離子信號(hào)。理解這種特異性可能在治療上具有重要意義,，這是因?yàn)樵谑艿桨柎暮Ｄ』虬d癇癥影響的大腦中,，星形膠質(zhì)細(xì)胞發(fā)送全局性信號(hào)，打個(gè)比方而言,，這種全局性信號(hào)更像是擴(kuò)音器廣播,，而健康星形膠質(zhì)細(xì)胞發(fā)送的信號(hào)類似于電話呼叫。
為了理解星形膠質(zhì)細(xì)胞信號(hào)如何受到調(diào)節(jié),，研究人員對(duì)單個(gè)mGluR5受體進(jìn)行量子點(diǎn)---當(dāng)激發(fā)時(shí)能夠發(fā)光的半導(dǎo)體納米晶體---標(biāo)記,，然后觀察這些受體如何穿過細(xì)胞膜。視頻畫面揭示mGluR5受體并不從射線狀臂到達(dá)胞體,。在正常星形膠質(zhì)細(xì)胞中,，mGluR5選擇性擴(kuò)散屏障能夠通過鈣離子信號(hào)區(qū)室化來允許每個(gè)射線狀臂獨(dú)立地調(diào)節(jié)它的接觸伙伴。
為了研究這種擴(kuò)散屏障的特征,，Mikoshiba研究團(tuán)隊(duì)試圖破壞它,。過度表達(dá)的mGluR5覆蓋著這種擴(kuò)散屏障，據(jù)此,，他們推斷這種屏障是由與mGluR5胞質(zhì)部分相互作用的蛋白組成的,。每個(gè)屏障蛋白與單個(gè)mGluR5分子配對(duì),，從而阻止它跨到胞體中,。然而,，屏障蛋白的數(shù)量是有限的，過量的mGluR5讓一些受體能夠自由地跨進(jìn)胞體,，因而能夠讓全局性信號(hào)通過星形膠質(zhì)細(xì)胞中的每個(gè)射線狀臂,。
阿爾茨海默病和癲癇癥實(shí)驗(yàn)性動(dòng)物模型證實(shí)星形膠質(zhì)細(xì)胞擁有高濃度的mGlu5分子。研究人員相信理解這種擴(kuò)散屏障的分子特征將有助于人們找到用于治療這些疾病的新靶標(biāo),。一旦揭示出這種屏障的分子特征,，他們希望構(gòu)建出一種缺乏星形膠質(zhì)細(xì)胞屏障蛋白的轉(zhuǎn)基因小鼠。Mikoshiba說,，“我們非常吃驚地了解到全局性星形膠質(zhì)細(xì)胞鈣離子信號(hào)對(duì)神經(jīng)元網(wǎng)絡(luò)和神經(jīng)-血管耦合(neuro-vascular coupling)的影響,。”(生物谷：Bioon.com)
本文編譯自A new starring role for astrocytes
doi: 10.1126/scisignal.2002498
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PMID:
Receptor-Selective Diffusion Barrier Enhances Sensitivity of Astrocytic Processes to Metabotropic Glutamate Receptor Stimulation
Misa Arizono1,2, Hiroko Bannai1*, Kyoko Nakamura3,4, Fumihiro Niwa1,5, Masahiro Enomoto1, Toru Matsu-ura1, Akitoshi Miyamoto1,2, Mark W. Sherwood1, Takeshi Nakamura3, and Katsuhiko Mikoshiba
Metabotropic glutamate receptor (mGluR)–dependent calcium ion (Ca2+) signaling in astrocytic processes regulates synaptic transmission and local blood flow essential for brain function. However, because of difficulties in imaging astrocytic processes, the subcellular spatial organization of mGluR-dependent Ca2+ signaling is not well characterized and its regulatory mechanism remains unclear. Using genetically encoded Ca2+ indicators, we showed that despite global stimulation by an mGluR agonist, astrocyte processes intrinsically exhibited a marked enrichment of Ca2+ responses. Immunocytochemistry indicated that these polarized Ca2+ responses could be attributed to increased density of surface mGluR5 on processes relative to the soma. Single-particle tracking of surface mGluR5 dynamics revealed a membrane barrier that blocked the movement of mGluR5 between the processes and the soma. Overexpression of mGluR or expression of its carboxyl terminus enabled diffusion of mGluR5 between the soma and the processes, disrupting the polarization of mGluR5 and of mGluR-dependent Ca2+ signaling. Together, our results demonstrate an mGluR5-selective diffusion barrier between processes and soma that compartmentalized mGluR Ca2+ signaling in astrocytes and may allow control of synaptic and vascular activity in specific subcellular domains.
