title: 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.
abstract: The aim of the present study was to investigate whether K(V)3.4 channel subunits are involved in neuronal death induced by neurotoxic beta-amyloid peptides (Abeta). In particular, to test this hypothesis, three main questions were addressed: 1) whether the Abeta peptide can up-regulate both the transcription/translation and activity of K(V)3.4 channel subunit and its accessory subunit, MinK-related peptide 2 (MIRP2); 2) whether the increase in K(V)3.4 expression and activity can be mediated by the nuclear factor-kappaB (NF-kappaB) family of transcriptional factors; and 3) whether the specific inhibition of K(V)3.4 channel subunit reverts the Abeta peptide-induced neurodegeneration in hippocampal neurons and nerve growth factor (NGF)-differentiated PC-12 cells. We found that Abeta(1-42) treatment induced an increase in K(V)3.4 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 Abeta peptide caused an increase in I(A) current amplitude carried by K(V)3.4 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-kappaB nuclear translocation with the cell membrane-permeable peptide SN-50 prevented the increase in K(V)3.4 protein and transcript expression. In addition, the SN-50 peptide was able to block Abeta(1-42)-induced increase in K(V)3.4 K(+) currents and to prevent cell death caused by Abeta(1-42) exposure. Finally, BDS-I produced a similar neuroprotective effect by inhibiting the increase in K(V)3.4 expression. As a whole, our data indicate that K(V)3.4 channels could be a novel target for Alzheimer's disease pharmacological therapy.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pannaccione
authors.forename: F
authors.initials: F
authors.lastname: Boscia
authors.forename: A
authors.initials: A
authors.lastname: Scorziello
authors.forename: A
authors.initials: A
authors.lastname: Adornetto
authors.forename: P
authors.initials: P
authors.lastname: Castaldo
authors.forename: R
authors.initials: R
authors.lastname: Sirabella
authors.forename: M
authors.initials: M
authors.lastname: Taglialatela
authors.forename: G F
authors.initials: GF
authors.lastname: Di Renzo
authors.forename: L
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003064:Cnidarian Venoms / Q000494:pharmacology; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012615:Sea Anemones / Q000737:chemistry; D051670:Shaw Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; C059796:BDS-I antiviral protein, Anemonia sulcata; D003064:Cnidarian Venoms; C492014:Kcnc4 protein, rat; D016328:NF-kappa B; D010446:Peptide Fragments; D010455:Peptides; D012333:RNA, Messenger; C118258:SN50 peptide; D051670:Shaw Potassium Channels; C075222:amyloid beta-protein (1-42)