9月5日加拿大研究人員發(fā)現(xiàn),，鹽的主要化學(xué)成分——鈉，是大腦中重要神經(jīng)遞質(zhì)——紅藻氨酸受體的一個(gè)獨(dú)特“開關(guān)”,。紅藻氨酸受體是大腦正常功能的基礎(chǔ),，與癲癇癥和神經(jīng)性疼痛等多種疾病相關(guān),。
麥吉爾大學(xué)藥理學(xué)和藥物治療學(xué)系教授德里克·鮑伊的此項(xiàng)發(fā)現(xiàn)，為大腦如何傳輸信息提供了不同的觀點(diǎn),。該項(xiàng)研究的重點(diǎn)在于開發(fā)藥物的新靶點(diǎn),，研究結(jié)果發(fā)表在《自然·結(jié)構(gòu)和分子生物學(xué)》雜志上。
紅藻氨酸受體活性的平衡是維持正常腦功能的關(guān)鍵,。例如,，癲癇是紅藻氨酸活性過度的結(jié)果。因此,，設(shè)計(jì)出能關(guān)閉這些活性的藥物將是非常有益的,。
鮑伊教授表示，人們幾十年來(lái)一直在推測(cè)所有大腦受體的開關(guān)應(yīng)位于神經(jīng)遞質(zhì)的結(jié)合部位,。不過,，新研究發(fā)現(xiàn)了一個(gè)可將單個(gè)鈉原子進(jìn)行結(jié)合的完全獨(dú)立的位點(diǎn)，其能控制紅藻氨酸受體何時(shí)打開和關(guān)閉,。
所謂的藥物“脫靶效應(yīng)”是現(xiàn)代醫(yī)學(xué)面臨的最大挑戰(zhàn)之一,。鈉開關(guān)對(duì)紅藻氨酸受體具有獨(dú)特性，意味著設(shè)計(jì)出旨在刺激這個(gè)開關(guān)的藥物,，不會(huì)在大腦中的其他地方起作用,。這將是藥物設(shè)計(jì)的重大進(jìn)步，因?yàn)楝F(xiàn)有藥物除了會(huì)在目標(biāo)位點(diǎn)產(chǎn)生作用,，往往還會(huì)影響許多其他位點(diǎn),，從而產(chǎn)生副作用。
圈點(diǎn)
食鹽是人們膳食中最常用的調(diào)味品,，也是人體中不可或缺的物質(zhì)成分,。如今，其主要化學(xué)成分鈉還被發(fā)現(xiàn)有助開發(fā)藥物的新靶點(diǎn),，更讓人對(duì)它刮目相看,。射擊賽場(chǎng)上的脫靶，頂多讓運(yùn)動(dòng)員極其懊惱罷了,，而醫(yī)學(xué)上的藥物“脫靶”,，所產(chǎn)生的副作用卻難以估量。文中的新發(fā)現(xiàn),，就好比幫藥物找到了精準(zhǔn)“打擊”病癥的小竅門,，這對(duì)減輕患者無(wú)謂的病痛無(wú)疑大有裨益。受此啟發(fā),，更加精確的藥物靶點(diǎn)或?qū)⒑糁觥＃ㄉ锕菳ioon.com）
生物谷推薦的英文摘要
Nature Structural & Molecular Biology doi:10.1038/nsmb.2654
Defining the structural relationship between kainate-receptor deactivation and desensitization
G Brent Dawe, Maria Musgaard, Elizabeth D Andrews, Bryan A Daniels, Mark R P Aurousseau, Philip C Biggin & Derek Bowie
Desensitization is an important mechanism curtailing the activity of ligand-gated ion channels (LGICs). Although the structural basis of desensitization is not fully resolved, it is thought to be governed by physicochemical properties of bound ligands. Here, we show the importance of an allosteric cation-binding pocket in controlling transitions between activated and desensitized states of rat kainate-type (KAR) ionotropic glutamate receptors (iGluRs). Tethering a positive charge to this pocket sustains KAR activation, preventing desensitization, whereas mutations that disrupt cation binding eliminate channel gating. These different outcomes explain the structural distinction between deactivation and desensitization. Deactivation occurs when the ligand unbinds before the cation, whereas desensitization proceeds if a ligand is bound without cation pocket occupancy. This sequence of events is absent from AMPA-type iGluRs; thus, cations are identified as gatekeepers of KAR gating, a role unique among even closely related LGICs.
