The potassium channel KCa3.1 constitutes a pharmacological target for astrogliosis associated with ischemia stroke

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0973-8) contains supplementary material, which is available to authorized users.

Ca2+-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling

“…It was reported that blockade of KCa3.1 significantly reduced neuronal loss and memory deficits in both APP/PS1 mice and SAMP8 mice [ 11 , 15 ]. Given that neuronal loss and decreased expression of synaptic proteins are likely correlated with the severity of AD [ 30 ], we compared expression levels of the neuron marker NeuN in the brain tissues of APP/PS1 mice with those of KCa3.1 −/− /APP/PS1 mutants.…”

“…The importance of KCa3.1 channels to CNS function is underscored by a series of studies implicating KCa3.1 in various diseases, including stroke/ischemia [ 32 , 33 ], AD [ 11 , 15 ], traumatic brain injury [ 34 ], and spinal cord injury [ 35 ]. These studies showed that upregulation of KCa3.1 activity can profoundly influence CNS pathology.…”

“…The 78-kDa glucose-regulated protein (GRP78) dissociates from PERK, ATF6, and IRE1 during ER stress, and then initiates proapoptotic signaling via activation of the CCAAT/enhancer-binding protein homologous protein (CHOP). Accumulating evidence suggests that Ca 2+ -dependent ER stress is correlated with reactive astrogliosis (RA) in both an AD mouse model and ischemic stroke [ 11 , 12 ]. In addition, the intermediate-conductance Ca 2+ -activated K + channel KCa3.1 is reported to be involved in cisplatin-initiated acute kidney injury [ 13 ] and the phenotypic switch of RA in ischemic stroke [ 12 ] via attenuation of ER stress.…”

Augmented astrocyte microdomain Ca2+ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

“…In addition to pharmacological agonists, astrocyte TRPV4 channels respond to epoxyeicosatrienoic acid (Baylie & Brayden, ), hemodynamic and mechanical stimuli (e.g., pressure, stretch, and swelling; Jo et al, ; Kim et al, ). While evidence support enhanced TRPV4 channel function in ischemia (Butenko et al, ; Rakers, Schmid, & Petzold, ; Yi et al, ), little is known on their function in hypertension.…”

“…While evidence support enhanced TRPV4 channel function in ischemia (Butenko et al, 2012;Rakers, Schmid, & Petzold, 2017;Yi et al, 2017), little is known on their function in hypertension.…”