Molecular Neuroprotection Induced by Zinc-Dependent Expression of Hepatitis C-Derived Protein NS5A Targeting Kv2.1 Potassium Channels
| Autor: | Shalom Mammen, Gabrielle J. Kosobucki, Chung-Yang Yeh, Elias Aizenman, Michael J. Palladino, Daniel T. Manjooran, Anthony J. Schulien, Jason A. Justice, Karen A. Hartnett-Scott |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Programmed cell death Cell Survival Cell Hepacivirus Viral Nonstructural Proteins Neuroprotection 03 medical and health sciences 0302 clinical medicine Shab Potassium Channels Neuropharmacology medicine Animals NS5A Transcription factor Cells Cultured Pharmacology Cerebral Cortex Neurons Cell Death Chemistry Neurodegeneration medicine.disease Hepatitis C Potassium channel Cell biology Rats Protein Transport Zinc 030104 developmental biology medicine.anatomical_structure Potassium Molecular Medicine Female 030217 neurology & neurosurgery Intracellular |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 367(2) |
| ISSN: | 1521-0103 |
| Popis: | We present the design of an innovative molecular neuroprotective strategy and provide proof-of-concept for its implementation, relying on the injury-mediated activation of an ectopic gene construct. As oxidative injury leads to the intracellular liberation of zinc, we hypothesize that tapping onto the zinc-activated metal regulatory element (MRE) transcription factor 1 system to drive expression of the Kv2.1-targeted hepatitis C protein NS5A (hepatitis C nonstructural protein 5A) will provide neuroprotection by preventing cell death–enabling cellular potassium loss in rat cortical neurons in vitro. Indeed, using biochemical and morphologic assays, we demonstrate rapid expression of MRE-driven products in neurons. Further, we report that MRE-driven NS5A expression, induced by a slowly evolving excitotoxic stimulus, functionally blocks injurious, enhanced Kv2.1 potassium whole-cell currents and improves neuronal viability. We suggest this form of “on-demand” neuroprotection could provide the basis for a tenable therapeutic strategy to prevent neuronal cell death in neurodegeneration. |
| Databáze: | OpenAIRE |
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