S1B-1 CLC-3 Chloride Channels in the Nervous System:Missed Targets in Cerebrovascular and Brain Diseases?

摘要

CLC-3 chloride(Cl-)channel,a member of an extended family of voltagegated CLC chloride channels and transporters,are ubiquitously expressed throughout the nervous system,including in the cerebrovascular smooth muscle cells(CVSMC)and neurons in the brain.CLC-3 chloride channels play critical roles in the regulation of vascular tone and cell volume regulation,migration,proliferation,and apoptosis.Remodeling of CLC-3 Cl-channels in CVSMC contributes significantly to the development of vascular pathology and remodeling and may be novel mechanisms for hypertension and stroke.Targeting Cl-channels may be a novel therapeutic strategy for the treatment of hypertension and stroke.CLC-3 Cl-channels are also involved in neuronal apoptosis and are important regulators of cell volume and hippocampal neuronal apoptosis.Expression of CLC-3 in the presynaptic vesicles determines quantal size of inhibitory transmission in the hippocampus through impact on GABAergic synaptic transmission.A distinct presynaptic CLC-3 dependent regulatory mechanism may represent a novel target for the regulation of synaptic vesicle acidification and filling.It extends the role of Cl-in inhibitory transmission from that of a postsynaptic permeant species to a presynaptic regulatory element.The CLC-3 Cl-channels are important targets for glioma and cancer therapy.CLC-3 channels(Cl.vol)/transporters may play important roles in the regulation of many cellular functions and integrate their physiological and pathological roles with multi-chloride channels,including TMEM16A(Cl.ca),CFTR at the phenomic level in the cerebrovascular and nervous system.Deep understandings of CLC-3 Cl-channels expression and function in the nervous system may provide novel molecular insights into the cerebrovascular disease and brain disease including brain cancers.