AMYLOID-BETA PROTEINS ACTIVATE CA2-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 degener ation, This study provides strong evidence for a novel cellular target for the actions of A beta, the phospholipase C-coupled, extracellular Ca2+-sensing receptor (CaR), We demonstrate that A beta s produce a C aR-mediated activation of a Ca2+-permeable, nonselective cation channe l (NCC), probably via elevation in cytosolic Ca2+ (Ca-i), 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 nontra nsfected human embryonic kidney (HEK293) cells, Thus aggregates of A b eta deposited on hippocampal neurons in AD could inappropriately activ ate the CaR, stimulating Ca2+-permeable channels and causing sustained elevation of Ca-i with resultant neuronal dysfunction. (C) 1997 Wiley -Liss, Inc.