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Up-Regulation and Increased Activity of K_V3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death

Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy

The aim of the present study was to investigate whether K_V3.4 channel subunits are involved in neuronal death induced by neurotoxic -amyloid peptides (A). In particular, to test this hypothesis, three main questions were addressed: 1) whether the A peptide can up-regulate both the transcription/translation and activity of K_V3.4 channel subunit and its accessory subunit, MinK-related peptide 2 (MIRP2); 2) whether the increase in K_V3.4 expression and activity can be mediated by the nuclear factor-B (NF-B) family of transcriptional factors; and 3) whether the specific inhibition of K_V3.4 channel subunit reverts the A peptide-induced neurodegeneration in hippocampal neurons and nerve growth factor (NGF)-differentiated PC-12 cells. We found that A_1–42 treatment induced an increase in K_V3.4 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 A peptide caused an increase in I_A current amplitude carried by K_V3.4 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-B nuclear translocation with the cell membrane-permeable peptide SN-50 prevented the increase in K_V3.4 protein and transcript expression. In addition, the SN-50 peptide was able to block A_1–42-induced increase in K_V3.4 K⁺ currents and to prevent cell death caused by A_1–42 exposure. Finally, BDS-I produced a similar neuroprotective effect by inhibiting the increase in K_V3.4 expression. As a whole, our data indicate that K_V3.4 channels could be a novel target for Alzheimer's disease pharmacological therapy.

Address correspondence to: Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Building 19, Via Pansini 5, 80131 Naples, Italy. E-mail: lannunzi{at}unina.it

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The MiRP2-Kv3.4 Potassium Channel: Muscling In on Alzheimer's Disease

Eun Choi and Geoffrey W. Abbott
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				E. Choi and G. W. Abbott The MiRP2-Kv3.4 Potassium Channel: Muscling In on Alzheimer's Disease Mol. Pharmacol., September 1, 2007; 72(3): 499 - 501. [Abstract] [Full Text] [PDF]