Inhibition of intracellular proton-sensitive Ca^(2+)-permeable TRPV3 channels protects against ischemic brain injury  

作　　者：Xiaoling Chen Jingliang Zhang KeWei Wang 

机构地区：[1]Department of Molecular and Cellular Pharmacology,State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [2]Department of Pharmacology,Qingdao University School of Pharmacy,Qingdao 266021,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第5期2330-2347,共18页药学学报（英文版）

基　　金：supported by grants awarded to KeWei Wang from National Natural Science Foundation of China (81903734 and81973299);the Ministry of Science and Technology of China(2018ZX09711001-004-006)。

摘　　要：Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-D-aspartate(NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca^(2+)-permeable transient receptor potential vanilloid 3(TRPV3) channel protects against cerebral ischemia/reperfusion(I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion(tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

关 键 词：TRPV3 Ca^(2+)influx ACIDOSIS Cerebral ischemia/reperfusion injury EXCITOTOXICITY Neural excitability Forsythoside B tMACO OGD TRP 

分 类 号：R965[医药卫生—药理学]