Rapid elevation of neuronal cytoplasmic calcium by apolipoprotein E peptide.
Apolipoprotein E (apoE) and certain peptides derived from it have been shown to exert neurotoxic effects in vitro, and apoE has been linked to the etiology of Alzheimer's disease. The mechanisms underlying these toxic and pathological effects are, however, not known. To approach this question, we have studied the effects of apoE peptides on the cytoplasmic calcium ([Ca2+]i) homeostasis of cultured cortical neurons. A tandem dimer repeat peptide (apoEdp) derived from the receptor binding domain of apoE was found to have a potent effect on elevation of [Ca2+]i calcium. The pathway by which apoEdp exerted this effect was shown to involve both the mobilization of intracellular calcium and the influx of extracellular calcium, although the effect on influx was more pronounced. Calcium mobilization occurs via a G-protein-linked phospholipase C (PLC) pathway, whereas calcium influx appears to involve a novel Co2+-sensitive channel. Both the mobilization and the influx of calcium require the binding of the apoE peptide to a membrane receptor because both pathways are blocked by antibody to low-density-lipoprotein receptor-related protein. The data suggest that the neurotoxic effects of apoE may be mediated by a persistent elevation of [Ca2+]i.
Wang
X S
XS
Neuroscience Graduate Program, University of Cincinnati College of Medicine, Ohio 45267-0524, USA.
Gruenstein
E
E
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology*; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D016257:Fura-2 / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000906:Antibodies; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004963:Estrenes; D005456:Fluorescent Dyes; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D002104:Cadmium; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D003035:Cobalt; D010738:Type C Phospholipases; D002118:Calcium; D016257:Fura-2