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Targeted inhibition of KC a3.1 attenuates TGF ‐β‐induced reactive astrogliosis through the Smad2/3 signaling pathway
Author(s) -
Yu Zhihua,
Yu Panpan,
Chen Hongzhuan,
Geller Herbert M.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12710
Subject(s) - astrogliosis , glial fibrillary acidic protein , microbiology and biotechnology , gliosis , chemistry , chondroitin sulfate proteoglycan , neurodegeneration , signal transduction , biology , endocrinology , immunology , medicine , neuroscience , extracellular matrix , proteoglycan , central nervous system , immunohistochemistry , disease
Reactive astrogliosis, characterized by cellular hypertrophy and various alterations in gene expression and proliferative phenotypes, is considered to contribute to brain injuries and diseases as diverse as trauma, neurodegeneration, and ischemia. KCa3.1 (intermediate‐conductance calcium‐activated potassium channel), a potassium channel protein, has been reported to be up‐regulated in reactive astrocytes after spinal cord injury in vivo . However, little is known regarding the exact role of KC a3.1 in reactive astrogliosis. To elucidate the role of KC a3.1 in regulating reactive astrogliosis, we investigated the effects of either blocking or knockout of KC a3.1 channels on the production of astrogliosis and astrocytic proliferation in response to transforming growth factor ( TGF )‐β in primary cultures of mouse astrocytes. We found that TGF ‐β increased KC a3.1 protein expression in astrocytes, with a concomitant marked increase in the expression of reactive astrogliosis, including glial fibrillary acidic protein and chondroitin sulfate proteoglycans. These changes were significantly attenuated by the KC a3.1 inhibitor 1‐((2‐chlorophenyl) (diphenyl)methyl)‐1H‐pyrazole ( TRAM ‐34). Similarly, the increase in glial fibrillary acidic protein and chondroitin sulfate proteoglycans in response to TGF ‐β was attenuated in KC a3.1 −/− astrocytes. TRAM ‐34 also suppressed astrocytic proliferation. In addition, the TGF ‐β‐induced phosphorylation of Smad2 and Smad3 proteins was reduced with either inhibition of KC a3.1 with TRAM ‐34 or in KC a3.1 −/− astrocytes. These findings highlight a novel role for the KC a3.1 channel in reactive astrogliosis phenotypic modulation and provide a potential target for therapeutic intervention for brain injuries.Reactive astrogliosis is characterized by the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans. We demonstrate that either pharmacological blockade or knockout of KCa3.1 channels reduces reactive gliosis in cultured astrocytes caused by TGF‐β, and also reduces TGF‐β‐induced phosphorylation of Smad2/3.