Up-regulation and increased activity of KV3.4 channels and their accessory subunit MinK-related peptide 2 induced by amyloid peptide are involved in apoptotic neuronal death

A. Pannaccione, F. Boscia, A. Scorziello, A. Adornetto, P. Castaldo, R. Sirabella, M. Taglialatela, G. F. Di Renzo, Lucio Annunziato

Research output: Contribution to journalArticlepeer-review

Abstract

The aim of the present study was to investigate whether KV3.4 channel subunits are involved in neuronal death induced by neurotoxic β-amyloid peptides (Aβ). In particular, to test this hypothesis, three main questions were addressed: 1) whether the Aβ peptide can up-regulate both the transcription/translation and activity of KV3.4 channel subunit and its accessory subunit, MinK-related peptide 2 (MIRP2); 2) whether the increase in KV3.4 expression and activity can be mediated by the nuclear factor-κB (NF-κB) family of transcriptional factors; and 3) whether the specific inhibition of KV3.4 channel subunit reverts the Aβ peptide-induced neurodegeneration in hippocampal neurons and nerve growth factor (NGF)-differentiated PC-12 cells. We found that Aβ1-42 treatment induced an increase in KV3.4 and MIRP2 transcripts and proteins, detected by reverse transcription-polymerase chain reaction and Western blot analysis, respectively, in NGF-differentiated PC-12 cells and hippocampal neurons. Patch-clamp experiments performed in whole-cell configuration revealed that the Aβ peptide caused an increase in IA current amplitude carried by KV3.4 channel subunits, as revealed by their specific blockade with blood depressing substance-I (BDS-I) in both hippocampal neurons and NGF-differentiated PC-12 cells. The inhibition of NF-κB nuclear translocation with the cell membrane-permeable peptide SN-50 prevented the increase in KV3.4 protein and transcript expression. In addition, the SN-50 peptide was able to block Aβ1-42-induced increase in KV3.4 K+ currents and to prevent cell death caused by Aβ1-42 exposure. Finally, BDS-I produced a similar neuroprotective effect by inhibiting the increase in KV3.4 expression. As a whole, our data indicate that KV3.4 channels could be a novel target for Alzheimer's disease pharmacological therapy.

Original languageEnglish
Pages (from-to)665-673
Number of pages9
JournalMolecular Pharmacology
Volume72
Issue number3
DOIs
Publication statusPublished - Sep 2007

ASJC Scopus subject areas

  • Pharmacology

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