中國科學(xué)院上海生命科學(xué)研究院神經(jīng)科學(xué)研究所神經(jīng)信號轉(zhuǎn)導(dǎo)研究組的杜婉璐、黃雋波和姚海蘭等研究生在王以政研究員的指導(dǎo)下發(fā)現(xiàn),，抑制瞬時受體電勢通道TRPC6蛋白降解保護缺血性腦損傷,。9月1日醫(yī)學(xué)雜志《臨床研究》（The Journal of Clinical Investigation）在線發(fā)表該工作,。文章探討了保持TRPC6通道活性治療腦中風(fēng)的可能性。
TAT-C6肽（包含calpain切割位點）保護大鼠缺血性腦損傷
腦中風(fēng)是世界范圍內(nèi)具有高致死率和致殘率的疾病,。中國每年患腦中風(fēng)的病人數(shù)很多,。其中缺血性腦中風(fēng)約占大多數(shù)，腦缺血大多是由于腦內(nèi)主要血管發(fā)生病變或阻塞,，造成腦組織血供減少或中斷所致,。受血供中斷直接影響的小部分區(qū)域，其神經(jīng)元壞死,，很難挽救,。而在其周圍區(qū)域（稱為半影區(qū)）的細(xì)胞，在恢復(fù)血供后也會由于興奮性氨基酸的毒性而逐漸死亡。半影區(qū)延遲性的神經(jīng)元死亡為腦中風(fēng)治療提供了可能的機會,。
瞬時受體電勢C（TRPC）通道蛋白,，在細(xì)胞膜上構(gòu)成非選擇性陽離子通道。這些通道存在于哺乳動物的各種細(xì)胞中,，擔(dān)負(fù)著多種生理功能,。其中的成員TRPC3和TRPC6對神經(jīng)元存活具有重要作用。通過大鼠腦中動脈栓塞的缺血模型,，作者們發(fā)現(xiàn)半影區(qū)神經(jīng)元TRPC6 蛋白被特異性地降解,。這一降解是通過NMDA受體的鈣離子依賴的中性蛋白水解酶（Calpain）介導(dǎo)的。他們發(fā)現(xiàn)了Calpain切割TRPC6蛋白的位點,，并依據(jù)其氨基酸序列合成了一段短肽,。這種短肽可以阻止缺血過程中TRPC6 蛋白的降解，保護了神經(jīng)細(xì)胞,。
該項研究提出阻止Calpain降解TRPC6可能成為治療缺血性腦損傷的新策略,，為治療腦中風(fēng)提供了新的思路。此項工作是該研究組研究TRPC6與神經(jīng)元存活又一新的發(fā)現(xiàn),。（生物谷Bioon.com）
更多閱讀
The Lancet：中風(fēng)搶救宜早不宜遲
JCBFM：黑巧克力或可保護中風(fēng)患者大腦
Cell：中風(fēng)的發(fā)病機制
The Lancet Neurology：阿司匹林加潘生丁可防中風(fēng)復(fù)發(fā)
怎樣預(yù)防中風(fēng)
Stroke：超重越多中風(fēng)風(fēng)險越高
生物谷推薦英文摘要：
J Clin Invest. doi:10.1172/JCI43165.
Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats
Wanlu Du, Junbo Huang, Hailan Yao, Kechun Zhou, Bo Duan and Yizheng Wang
Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, State Key Laboratory of Neuroscience, The Graduate School, Chinese Academy of Sciences, Shanghai, China.
Brain injury after focal cerebral ischemia, the most common cause of stroke, develops from a series of pathological processes, including excitotoxicity, inflammation, and apoptosis. While NMDA receptors have been implicated in excitotoxicity, attempts to prevent ischemic brain damage by blocking NMDA receptors have been disappointing. Disruption of neuroprotective pathways may be another avenue responsible for ischemic damage, and thus preservation of neuronal survival may be important for prevention of ischemic brain injury. Here, we report that suppression of proteolytic degradation of transient receptor potential canonical 6 (TRPC6) prevented ischemic neuronal cell death in a rat model of stroke. The TRPC6 protein level in neurons was greatly reduced in ischemia via NMDA receptor–dependent calpain proteolysis of the N-terminal domain of TRPC6 at Lys16. This downregulation was specific for TRPC6 and preceded neuronal death. In a rat model of ischemia, activating TRPC6 prevented neuronal death, while blocking TRPC6 increased sensitivity to ischemia. A fusion peptide derived from the calpain cleavage site in TRPC6 inhibited degradation of TRPC6, reduced infarct size, and improved behavioral performance measures via the cAMP response element–binding protein (CREB) signaling pathway. Thus, TRPC6 proteolysis contributed to ischemic neuronal cell death, and suppression of its degradation preserved neuronal survival and prevented ischemic brain damage.
