title: Calpain-Dependent ErbB4 Cleavage Is Involved in Brain Ischemia-Induced Neuronal Death.
abstract: Disturbance of neuregulin-1β/ErbB4 signaling is considered to be associated with brain ischemia, but the mechanisms of this disruption are largely unknown. In the present study, we provide evidence that degradation of ErbB4 is involved in neuronal cell death in response to ischemia. Our data showed that the application of neuregulin-1β provided significant protection against oxygen-glucose deprivation (OGD)-induced neuronal death as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, annexin V/propidium iodide flow cytometry analysis and terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) staining. Furthermore, neuregulin-1β treatment significantly reduced the infarct volume of ischemic mice, and this result was not seen in the ErbB4 knockout mice. We found that brain ischemia induced the breakdown of ErbB4 in a time-dependent manner in vivo, but not that of ErbB2. In vitro studies further indicated that recombinant calpain induced the cleavage of ErbB4 in a dose-dependent way, whereas the calpain inhibitor significantly reduced the OGD-induced ErbB4 breakdown. Additionally, OGD-induced apoptosis was partially abolished by transfection with the ErbB4E872K mutant. Taken together, neuregulin-1β elicits its neuroprotective effect in an ErbB4-dependent manner, and the cleavage of ErbB4 by calpain contributes to a neuronal cell death cascade during brain ischemia.
authors.affiliation: School of Medicine, Zhejiang University City College, Hangzhou, China.|Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Ying-mei
authors.initials: YM
authors.lastname: Lu
authors.affiliation: School of Medicine, Zhejiang University City College, Hangzhou, China.
authors.forename: Yin-ping
authors.initials: YP
authors.lastname: Gao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Rong-rong
authors.initials: RR
authors.lastname: Tao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Mei-hua
authors.initials: MH
authors.lastname: Liao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Ji-yun
authors.initials: JY
authors.lastname: Huang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China. lixm@zju.edu.cn.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Li
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D020890:Neuregulin-1 / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010100:Oxygen; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D014162:Transfection
chemical_list: D020890:Neuregulin-1; D018696:Neuroprotective Agents; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D002154:Calpain; D005947:Glucose; D010100:Oxygen
keywords: Brain ischemia; Calpain; Cleavage; ErbB4; Neuregulin-1β