The Regulation Of KCa3.1 In The Process Of Reactive Astrogliosis Associated With Ischemic Stroke

Ischemic stroke is mainly due to cerebrovascular stenosis or occlusion of the arterial blood supply to part of the brain,leading to ischemia,hypoxia,softening or even necrosis in the brain tissue,and resulting in cerebrovascular dysfunction.Because of various restrictions in thrombolytic therapy and the current clinical trials aimed at reducing cerebral ischemic injury by neuroprotective drugs have failed,there is an urgent need for new targets and drugs for neuroprotection.As an important component of neurovascular unit（NVU）,astrocytes respond to different neurological diseases including ischemic stroke through a process termed as reactive astrogliosis.Reactive astrogliosis is an adaptive defense response that is both beneficial and detrimental to the injured CNS.KCa3.1,a voltage-independent calcium-activated K⁺channel,plays an important role in modulating calcium-signaling and membrane potential.Activation of KCa3.1 by elevated intracellular calcium maintains a negative membrane potential,which provides driving force for Ca²⁺influx,leading to continuous activation of KCa3.1 and calcium metabolism imbalance in cells.It has been shown that cerebral ischemia associated with reactive astrogliosis,whether KCa3.1 channel is involved in this pathological process is not well known.In this study,the model of permanent middle cerebral artery occlusion in mice and oxygen and glucose deprivation in primary astrocytes were constructed to explore the role of Ka3.1 channel on reactive astrogliosis in cerebral ischemia.We reported that the expression of KCa3.1 in the brains after permanent middle cerebral artery occlusion in mice was significantly up-regulated and mainly resulted from reactive astrocytes.Genetic KCa3.1-deficiency reduced gliosis and neuronal loss induced by ischemic stroke.KCa3.1 was involved in reactive astrogliosis during cerebral ischemia through KCa3.1-TRPV4 complex via MAPK/ERK,JNK/c-Jun and ERS signaling pathways.This study demonstrated the regulation of KCa3.1 in the process of reactive astrogliosis associated with ischemic stroke,which provide a new therapeutic target for clinical neuroprotection of cerebral ischemia.