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Molecular Pharmacology

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Research ArticleArticle

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 and L. Annunziato
Molecular Pharmacology September 2007, 72 (3) 665-673; DOI: https://doi.org/10.1124/mol.107.034868
A. Pannaccione
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F. Boscia
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A. Scorziello
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A. Adornetto
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P. Castaldo
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R. Sirabella
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M. Taglialatela
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G. F. Di Renzo
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L. Annunziato
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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.

Footnotes

  • This study was supported by grants from the Italian Ministry of Health Programma Speciale art. 12bis comma 6, D. Lgs. 229/99; Special Project “Alzheimer 2001/2004” (to L.A. and M.T.), COFIN-MIUR 2002 (to L.A.), COFIN 2004 (to L.A.), PNR-FIRB RBNE01E7YX_007 2001, Regione Campania GEAR, Ricerca Finalizzata Ministero della Salute legge 502/92 “Geni Vulnerabiltà e di Riparazione DNA” (to L.A.), and POP and legge 41 from Regione Campania, 12th Italian-Chinese executive program for scientific and technological cooperation for the period 2006 to 2009 from the Italian Foreign Ministry (to L.A.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.034868.

  • ABBREVIATIONS: KV channels, voltage-gated K+ channels; Aβ, β-amyloid peptide; Aβ1–42, β-amyloid peptide 1–42; AD, Alzheimer's disease; BDS-I, blood depressing substance-I; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IA, fast inactivating K+ currents; MIRP, MinK-related peptide; NGF, nerve growth factor; NF-κB, nuclear factor κB; PBS, phosphate-buffered saline; RT-PCR, reverse transcription polymerase chain reaction; ANOVA, analysis of variance; bp, base pair(s); SN-50, NF-κB cell-permeable inhibitory peptide (AAVALLPAVLLALLAPVQRKRQKLMP).

    • Received February 7, 2007.
    • Accepted May 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (3)
Molecular Pharmacology
Vol. 72, Issue 3
1 Sep 2007
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Research ArticleArticle

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 and L. Annunziato
Molecular Pharmacology September 1, 2007, 72 (3) 665-673; DOI: https://doi.org/10.1124/mol.107.034868

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Research ArticleArticle

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 and L. Annunziato
Molecular Pharmacology September 1, 2007, 72 (3) 665-673; DOI: https://doi.org/10.1124/mol.107.034868
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