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 ( A beta). In particular, to test this hypothesis, three main questions were addressed: 1) whether the A beta 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- kappa B ( NF- kappa B) family of transcriptional factors; and 3) whether the specific inhibition of K V 3.4 channel subunit reverts the A beta peptide- induced neurodegeneration in hippocampal neurons and nerve growth factor ( NGF)- differentiated PC- 12 cells. We found that A beta 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 A beta 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- kappa B 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 A beta (1 - 42)- induced increase in K V 3.4 K (+) currents and to prevent cell death caused by A beta (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.
Up-regulation and increased activity of K(V)3.4 channels and their accessory subunit MinK-Related peptide 2 induced by amyloid peptide are involved in apoptotic neuronal death
TAGLIALATELA, Maurizio;
2007-01-01
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 ( A beta). In particular, to test this hypothesis, three main questions were addressed: 1) whether the A beta 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- kappa B ( NF- kappa B) family of transcriptional factors; and 3) whether the specific inhibition of K V 3.4 channel subunit reverts the A beta peptide- induced neurodegeneration in hippocampal neurons and nerve growth factor ( NGF)- differentiated PC- 12 cells. We found that A beta 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 A beta 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- kappa B 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 A beta (1 - 42)- induced increase in K V 3.4 K (+) currents and to prevent cell death caused by A beta (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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
