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J. Biol. Chem., Vol. 277, Issue 17, 14458-14466, April 26, 2002

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₂-Macroglobulin Exposure Reduces Calcium Responses to N-Methyl-D-Aspartate via Low Density Lipoprotein Receptor-related Protein in Cultured Hippocampal Neurons^*

Zhihua Qiu^§, Dudley K. Strickland^¶, Bradley T. Hyman, and G. William Rebeck

From the  Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and ^¶ Holland Laboratory, American Red Cross, Rockville, Maryland 20855

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 ₂-macroglobulin (2M*), a ligand of LRP, on intracellular calcium signaling in cultured rat hippocampal neurons. Neuronal effects of 2M* (50 nM) were assessed by a comparison of calcium signals produced in control and 2M*-pretreated neurons by N-methyl-D-aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. 2M* pretreatment significantly decreased the calcium signals to NMDA, whereas little change was observed for the signals to -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. Native 2M, which is not a ligand for LRP, did not affect signals to NMDA. The receptor-associated protein prevented 2M*-induced decrease of calcium responses to NMDA, suggesting that 2M* exerted its effects through an LRP-mediated pathway. Experiments changing calcium sources demonstrated that 2M* 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 2M* caused a reduction in the levels of the NMDA receptor subunit, NMDAR1. These results suggest that 2M* can alter the neuronal response to excitatory neurotransmitters and that 2M* pretreatment selectively reduced the calcium responses to NMDA by down-regulating the NMDA receptor.

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