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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.

SUBMITTER: Winkelmann A

PROVIDER: S-EPMC4669822 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain.

Winkelmann A A Semtner M M Meier J C JC

Cell death & disease 20150604

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 v ...[more]

PMID: 26043076

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Project description:Exceptional mechanical and electrical properties of carbon nanotubes (CNT) have attracted neuroscientists and neural tissue engineers aiming to develop novel devices that interface with nervous tissues. In the central nervous system (CNS), the perinatal chloride shift represents a dynamic change that forms the basis for physiological actions of γ-aminobutyric acid (GABA) as an inhibitory neurotransmitter, a process of fundamental relevance for normal functioning of the CNS. Low intra-neuronal chloride concentrations are maintained by a chloride-extruding transporter, potassium chloride cotransporter 2 (KCC2). KCC2's increasing developmental expression underlies the chloride shift. In neural injury, repressed KCC2 expression plays a co-contributory role by corrupting inhibitory neurotransmission. Mechanisms of Kcc2 up-regulation are thus pertinent because of their medical relevance, yet they remain elusive. Here, it is shown that primary CNS neurons originating from the cerebral cortex, cultured on highly-conductive few-walled-CNT (fwCNT) have a strikingly accelerated chloride shift caused by increased KCC2 expression. KCC2 upregulation is dependent on neuronal voltage-gated calcium channels (VGCC) and, furthermore, on calcium/calmodulin-dependent kinase II, which is linked to VGCC-mediated calcium-influx. It is also demonstrated that accelerated Kcc2 transcription in brain-slices prepared from genetically-engineered reporter mice, in which Kcc2 promoter drives luciferase, when the cerebral cortex of these mice is exposed to fwCNT-coated devices. Based on these findings, whether fwCNT can enhance neural engineering devices for the benefit of neural injury conditions associated with elevated neuronal intracellular chloride concentration-such as pain, epilepsy, traumatic neural injury and ischemia-can now be addressed. Taken together, our novel insights illustrate how fwCNTs can promote low neuronal chloride in individual neurons and thus inhibitory transmission in neural circuits.

Dataset Information

Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain.

Publications

Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain.

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