Presenilin-1 mutations alter K+ currents in the human neuroblastoma cell line, SH-SY5Y.
Mutations in presenilin 1 (PS1) are the major cause of autosomal dominant Alzheimer's disease. We have measured the voltage-gated K+ current in the human neuroblastoma cell line SH-SY5Y using whole-cell patch-clamp. When cells were stably transfected to over-express PS1, no change in K+ current was observed. However, over-expression of a deletion mutation (deltaE9) in PS1 led to a decreased K+ current. These changes were channel specific since no change in the Na+ current could be observed in the same cells. Confocal microscopy revealed that the K(V)3.1 K+ channel subunit had a diminished plasma membrane distribution when the deltaE9 over-expressing cells were compared to control cells. Intracellular retention of Kv3.1 is consistent with the notion that PS1 can modulate the activity and trafficking of ion channels in central neurones and implicates a compromise in electrical signalling as an underlying factor in the pathogenesis of familial Alzheimer's disease.
Plant
Leigh D
LD
School of Biomedical Sciences, University of Leeds, Leeds, UK.
Boyle
John P
JP
Thomas
Natasha M
NM
Hipkins
Nick J
NJ
Benedikz
Eirikur
E
Hooper
Nigel M
NM
Henderson
Zaineb
Z
Vaughan
Peter F T
PF
Peers
Chris
C
Cowburn
Richard F
RF
Pearson
Hugh A
HA
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics*; D009447:Neuroblastoma; D009479:Neuropeptides / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D053764:Presenilin-1; D051670:Shaw Potassium Channels; D015222:Sodium Channels / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D009479:Neuropeptides; C508853:PSEN1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D053764:Presenilin-1; D051670:Shaw Potassium Channels; D015222:Sodium Channels; D011188:Potassium