title: Activation of the KCa3.1 channel contributes to traumatic scratch injury-induced reactive astrogliosis through the JNK/c-Jun signaling pathway.
abstract: Reactive astrogliosis is widely considered to contribute to pathogenic responses to stress and brain injury and to diseases as diverse as ischemia and neurodegeneration. We previously found that expression of the intermediate-conductance calcium-activated potassium channel (KCa3.1) involved in TGF-β-activated astrogliosis. In the present study, we investigated whether migration of cortical astrocytes following mechanical scratch injury involves the KCa3.1 channel, which contributes to Ca(2+)-mediated migration in other cells. We found that scratch injury increased the expression of KCa3.1 protein in reactive astrocytes. Application of the KCa3.1 blocker TRAM-34 decreased glial fibrillary acidic protein (GFAP) expression and slowed migration in a concentration-dependent manner. Application of the Ca(2+) chelators, EGTA and BAPTA-AM, also slowed the migration of astrocytes. Blockade or genetic deletion of KCa3.1 both slowed and dramatically reduced the scratch injuries induced the sharp rise in astrocytes Ca(2+) concentrations. The scratch injury-induced phosphorylation of JNK and c-Jun proteins was also attenuated both by blockade of KCa3.1 with TRAM-34 and in KCa3.1(-/-) astrocytes. Using KCa3.1 knockout mice, we further confirmed that deletion of KCa3.1 reduced expression of GFAP in an in vivo stab wound model. Taken together, our findings highlight a novel role for KCa3.1 in phenotypic modulation of reactive astrocytes and in astrocyte mobilization in response to mechanical stress, providing a potential target for therapeutic intervention in brain injuries.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Mengni
authors.initials: M
authors.lastname: Yi
authors.affiliation: Central Laboratory, Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Dou
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yuzhihua@shsmu.edu.cn.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: hongzhuan_chen@hotmail.com.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D065096:Calcium Chelating Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism* / Q000503:physiopathology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000494:pharmacology; D013312:Stress, Physiological; D014732:Vibration
chemical_list: D065096:Calcium Chelating Agents; D005904:Glial Fibrillary Acidic Protein; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; C411671:TRAM 34; D004533:Egtazic Acid; D002118:Calcium
keywords: Astrocytes; Calcium; KCa3.1; Migration; Reactivity