title: Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain.
abstract: Neurodegeneration is a serious issue of neurodegenerative diseases including epilepsy. Downregulation of the chloride transporter KCC2 in the epileptic tissue may not only affect regulation of the polarity of GABAergic synaptic transmission but also neuronal survival. Here, we addressed the mechanisms of KCC2-dependent neuroprotection by assessing truncated and mutated KCC2 variants in different neurotoxicity models. The results identify a threonine- and tyrosine-phosphorylation-resistant KCC2 variant with increased chloride transport activity, but they also identify the KCC2 N-terminal domain (NTD) as the relevant minimal KCC2 protein domain that is sufficient for neuroprotection. As ectopic expression of the KCC2-NTD works independently of full-length KCC2-dependent regulation of Cl(-) transport or structural KCC2 C-terminus-dependent regulation of synaptogenesis, our study may pave the way for a selective neuroprotective therapeutic strategy that will be applicable to a wide range of neurodegenerative diseases.
authors.affiliation: RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Winkelmann
authors.affiliation: RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Semtner
authors.affiliation: 1] RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany [2] Division of Cell Physiology, TU Braunschweig, Zoological Institute, Braunschweig 38106, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Meier
mesh_terms: D000818:Animals; D002470:Cell Survival; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology*; D017136:Ion Transport / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D000066829:Neuroprotection / Q000502:physiology*; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D000096922:K Cl- Cotransporters
chemical_list: D018009:Receptors, Glycine; D027981:Symporters; D000096922:K Cl- Cotransporters