The Experts below are selected from a list of 15114 Experts worldwide ranked by ideXlab platform
Xinyue Qin - One of the best experts on this subject based on the ideXlab platform.
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rgma mediates reactive Astrogliosis and glial scar formation through tgfβ1 smad2 3 signaling after stroke
Cell Death & Differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
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RGMa mediates reactive Astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke
Cell death and differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
Philippe P Monnier - One of the best experts on this subject based on the ideXlab platform.
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rgma mediates reactive Astrogliosis and glial scar formation through tgfβ1 smad2 3 signaling after stroke
Cell Death & Differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
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RGMa mediates reactive Astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke
Cell death and differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
Jason Charish - One of the best experts on this subject based on the ideXlab platform.
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rgma mediates reactive Astrogliosis and glial scar formation through tgfβ1 smad2 3 signaling after stroke
Cell Death & Differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
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RGMa mediates reactive Astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke
Cell death and differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
Rongrong Zhang - One of the best experts on this subject based on the ideXlab platform.
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rgma mediates reactive Astrogliosis and glial scar formation through tgfβ1 smad2 3 signaling after stroke
Cell Death & Differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
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RGMa mediates reactive Astrogliosis and glial scar formation through TGFβ1/Smad2/3 signaling after stroke
Cell death and differentiation, 2018Co-Authors: Rongrong Zhang, Fei Xie, Yiliang Zhong, Yu Wang, Jinzhou Feng, Jason Charish, Philippe P Monnier, Xinyue QinAbstract:In response to stroke, astrocytes become reactive Astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive Astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive Astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive Astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive Astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive Astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.
Herbert M. Geller - One of the best experts on this subject based on the ideXlab platform.
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The potassium channel KCa3.1 constitutes a pharmacological target for Astrogliosis associated with ischemia stroke
Journal of Neuroinflammation, 2017Co-Authors: Mengni Yi, Xiaoling Gao, Gaoxian Chen, Tianjiao Wei, Yanxia Wang, Hongzhuan Chen, Qin Lu, Herbert M. Geller, Zhihua YuAbstract:BackgroundReactive Astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced Astrogliosis in vitro and also contributed to Astrogliosis-mediated neuroinflammation in neurodegeneration disease.MethodsWild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro.ResultsImmunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive Astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of Astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive Astrogliosis.ConclusionsOur data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.
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the potassium channel kca3 1 constitutes a pharmacological target for Astrogliosis associated with ischemia stroke
Journal of Neuroinflammation, 2017Co-Authors: Mengni Yi, Gaoxian Chen, Yanxia Wang, Hongzhuan Chen, Qin Lu, Herbert M. Geller, Zhihua YuAbstract:Reactive Astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced Astrogliosis in vitro and also contributed to Astrogliosis-mediated neuroinflammation in neurodegeneration disease. Wild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro. Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive Astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of Astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive Astrogliosis. Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.
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kca3 1 constitutes a pharmacological target for Astrogliosis associated with alzheimer s disease
Molecular and Cellular Neuroscience, 2016Co-Authors: Mengni Yi, Zhihua Yu, Panpan Yu, Qin Lu, Herbert M. Geller, Hongzhuan ChenAbstract:Abstract Alzheimer's disease (AD) is the most common type of dementia and is characterized by a progression from decline of episodic memory to a global impairment of cognitive function. Astrogliosis is a hallmark feature of AD, and reactive gliosis has been considered as an important target for intervention in various neurological disorders. We previously found in astrocyte cultures that the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 was increased in reactive astrocytes induced by TGF-β, while pharmacological blockade or genetic deletion of KCa3.1 attenuated Astrogliosis. In this study, we sought to suppress reactive gliosis in the context of AD by inhibiting KCa3.1 and evaluate its effects on the cognitive impairment using murine animal models such as the senescence-accelerated mouse prone 8 (SAMP8) model that exhibits some AD-like symptoms. We found KCa3.1 expression was increased in reactive astrocytes as well as neurons in the brains of both SAMP8 mice and Alzheimer's disease patients. Blockade of KCa3.1 with the selective inhibitor TRAM-34 in SAMP8 mice resulted in a decrease in Astrogliosis as well as microglia activation, and moreover an attenuation of memory deficits. Using KCa3.1 knockout mice, we further confirmed that deletion of KCa3.1 reduced the activation of astrocytes and microglia, and rescued the memory loss induced by intrahippocampal Aβ1–42 peptide injection. We also found in astrocyte cultures that blockade of KCa3.1 or deletion of KCa3.1 suppressed Aβ oligomer-induced Astrogliosis. Our data suggest that KCa3.1 inhibition might represent a promising therapeutic strategy for AD treatment.
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targeted inhibition of kca3 1 attenuates tgf β induced reactive Astrogliosis through the smad2 3 signaling pathway
Journal of Neurochemistry, 2014Co-Authors: Hongzhuan Chen, Herbert M. GellerAbstract:Astrocytes, the predominant glial cell population in the mammalian central nervous system (CNS), play essential roles not only in physiological functions, such as synaptic plasticity (Dallerac et al. 2013) and hemodynamic responses (Petzold and Murthy 2011),but also in pathophysiological conditions. In response to brain injuries and diseases as diverse as trauma, neurodegeneration, and ischemia, astrocytes undergo characteristic phenotypic modulation known as reactive Astrogliosis (Silver and Miller 2004, Sofroniew 2009). Gliosis normally involves cellular hypertrophy and various alterations in gene expression and can include astrocyte proliferation after particularly severe insults (Sofroniew 2005). Glial fibrillary acidic protein (GFAP) expression by astrocytes is a prototypic marker of reactive Astrogliosis (Bignami and Dahl 1974, Bignami et al. 1972) and a characteristic response to inflammation after CNS injury. In addition, reactive Astrogliosis generates increased expression of extracellular matrix (ECM) molecules, including chondroitin sulfate proteoglycans (CSPGs), a class of glycol-conjugates (McKeon et al., 1999). CSPG overexpression is linked to glial scar formation, which impedes axonal regeneration and outgrowth (Fitch and Silver 1997, Snow et al. 1990). Despite the importance of this process, the molecular mechanisms governing reactive Astrogliosis and the role of reactive astrocytes require further clarification. The intermediate-conductance calcium-activated potassium channel, composed of four KCa3.1 subunits and 4 calmodulin molecules, is expressed in T cells, macrophages, mast cells, epithelium, fibroblasts, and both normal and asthmatic human airway smooth muscle cells (Toyama et al. 2008, Yu et al. 2013b), where they can communicate directly between Ca2+ signaling pathways and changes in membrane potential required for various cellular processes, such as activation, proliferation, and migration (Yu et al. 2013a). Small molecules and peptide toxins such as triarylmethanes (TRAM-34) have been explored as specific selective KCa3.1 blockers. They inhibit airway smooth muscle cell proliferation, fibrocyte migration, macrophage function and T cell activation (Huang et al. 2013, Di et al. 2010). KCa3.1 is a potential molecular target for pharmacological intervention in vascular restenosis, asthma, prostate cancer, and autoimmune disease (Toyama et al. 2008, Bradding and Wulff 2009). Recently, Bouhy et al. (2011) have reported that KCa3.1 was up-regulated at the mRNA and protein levels after spinal cord injury (SCI), and reactive astrocytes were the main cell type with increased KCa3.1. Furthermore, blockade of KCa3.1 reduced tissue and axonal loss, and improved neuronal survival and locomotor recovery (Bouhy et al. 2011). KCa3.1 blockers also decreased Astrogliosis in the brains of glioblastoma multiforme-xenografted mice (D’Alessandro et al. 2013). We thus hypothesized that KCa3.1 might be involved in regulating reactive Astrogliosis. Transforming growth factor (TGF)-β is rapidly up-regulated after CNS injury in vivo and is important both as a soluble regulator of ECM formation and in inducing reactive Astrogliosis (Logan et al. 1992, Logan et al. 1994, Wang et al. 2008). Emerging evidence has shown that the primary signaling pathway mediated by TGF-β is the Smad pathway (Derynck and Zhang 2003). TGF-β binds to a heteromeric TGF-β receptor complex consisting of two type I and two type II serine/threonine kinase receptors (TβRI/TβR II), and then the activated type I receptor subsequently phosphorylates Smads, complex with the co-Smad Smad4 and translocate to the nucleus to regulate the downstream transcription factors (Ross and Hill 2008). TGF-β can activate many other pathways including the MAPK and PI3 kinase pathways in a Smad-independent manner (Moustakas and Heldin 2005). It has been shown that TGF-β induction of CSPG expression in astrocytes is Smad2 and Smad3 dependent in vitro (Susarla et al. 2011). In this study, we present evidence that the KCa3.1 channels are required for reactive Astrogliosis in response to TGF-β stimuli. We found that TGF-β increased the expression of KCa3.1 channels with a concomitant marked increase in the expression of GFAP and CSPGs, as well as increased astrocyte proliferation. These changes in response to TGF-β were reduced by pharmacological blockade or gene knockout (KO) of KCa3.1. In addition, blockade of KCa3.1 suppressed Astrogliosis by inhibiting TGF-β-induced Smad2 and Smad3 activation.
