Amyloid-beta proteins activate Ca(2+)-permeable channels through calcium-sensing receptors.
The amyloid-beta peptides (A beta) are produced in excess in Alzheimer's disease (AD) and may contribute to neuronal dysfunction and degeneration. This study provides strong evidence for a novel cellular target for the actions of A beta, the phospholipase C-coupled, extracellular Ca(2+)-sensing receptor (CaR). We demonstrate that A beta(s) produce a CaR-mediated activation of a Ca(2+)-permeable, nonselective cation channel (NCC), probably via elevation in cytosolic Ca2+ (Cai), in cultured hippocampal pyramidal neurons from normal rats and from wild type mice but not those from mice with targeted disruption of the CaR gene (CaR -/-). A beta(s) also activate NCC in CaR-transfected but not in nontransfected human embryonic kidney (HEK293) cells. Thus aggregates of A beta deposited on hippocampal neurons in AD could appropriately activate the CaR, stimulating Ca(2+)-permeable channels and causing sustained elevation of Cai with resultant neuronal dysfunction.
Ye
C
C
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Ho-Pao
C L
CL
Kanazirska
M
M
Quinn
S
S
Rogers
K
K
Seidman
C E
CE
Seidman
J G
JG
Brown
E M
EM
Vassilev
P M
PM
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D051379:Mice; D051381:Rats
D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D007473:Ion Channels; D002118:Calcium