title: alpha 2-Macroglobulin exposure reduces calcium responses to N-methyl-D-aspartate via low density lipoprotein receptor-related protein in cultured hippocampal neurons.
abstract: There is increasing evidence that the low-density lipoprotein receptor-related protein (LRP) can function as a signaling link in the central nervous system. To investigate the pathophysiological role of LRP in the central nervous system, we examined the effects of activated alpha(2)-macroglobulin (alpha2M*), a ligand of LRP, on intracellular calcium signaling in cultured rat hippocampal neurons. Neuronal effects of alpha2M* (50 nm) were assessed by a comparison of calcium signals produced in control and alpha2M*-pretreated neurons by N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. alpha2M* pretreatment significantly decreased the calcium signals to NMDA, whereas little change was observed for the signals to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. Native alpha2M, which is not a ligand for LRP, did not affect signals to NMDA. The receptor-associated protein prevented alpha2M*-induced decrease of calcium responses to NMDA, suggesting that alpha2M* exerted its effects through an LRP-mediated pathway. Experiments changing calcium sources demonstrated that alpha2M* pretreatment altered calcium responses to NMDA by primarily changing extracellular calcium influx and subsequently affecting calcium release from intracellular calcium stores. Immunoblot analysis demonstrated that alpha2M* caused a reduction in the levels of the NMDA receptor subunit, NMDAR1. These results suggest that alpha2M* can alter the neuronal response to excitatory neurotransmitters and that alpha2M* pretreatment selectively reduced the calcium responses to NMDA by down-regulating the NMDA receptor.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. qiu@helix.mgh.harvard.edu
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Qiu
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000511:alpha-Macroglobulins; D016202:N-Methylaspartate; D011189:Potassium Chloride; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002118:Calcium