Received for publication February 8, 2007.
Revised May 10, 2007.
Accepted for publication May 10, 2007.

Up-regulation and increased activity of K_V3.4 channels and its accessory subunit MIRP2 induced by amyloid peptide is involved in apoptotic neuronal death

Abstract

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). Particularly, to test this hypothesis, three main questions were addressed: (1) whether the A peptide can up-regulate both the transcription/translocation and activity of K_V3.4 channel subunit, as well as its accessory subunit MIRP2; (2) whether the increase in K_V3.4 expression and activity can be mediated by the NF-kB family of transcriptional factors; (3) whether the specific inhibition of K_V3.4 channel subunit reverts the Anpeptide-induced neurodegeneration in hippocampal neurons and NGF-differentiated PC-12 cells. We found that A_1-42 treatment induced an increase in K_V3.4 and MIRP-2 transcripts and proteins, detected by RT-PCR and by Western blot analysis, 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 BDS-I both in hippocampal neurons and NGF-differentiated PC-12 cells. The inhibition of NF-kB 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 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 toxin produced a similar neuroprotective effect by inhibiting the increase in K_V3.4 expression. Collectively, our data indicate that K_V3.4 channels could be a novel target for therapeutic strategy of AD.

Key words: Ion channel regulation, Potassium, NFkappaB, Fluorescence techniques, Immunocytochemistry

This article has been cited by other articles:

				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]