The endocytic receptor protein LRP also mediates neuronal calcium signaling via N-methyl-D-aspartate receptors

The low density lipoprotein receptor-related protein (LRP) is an endocytic receptor that is a member of the low density lipoprotein receptor family. W e report that the LRP ligand, activated alpha(2)-macroglobulin (alpha(2)M*) , induces robust calcium influx in cultured primary neurons, but not in non neuronal LRP-containing cells in the same culture. The calcium influx is me diated through N-methyl-D-aspartate receptor channels, which explains the n euron specificity of the response. Microapplication of alpha(2)M* leads to a localized response at the site of application that dissipates rapidly, su ggesting that the calcium signal is temporally and spatially discrete. Calc ium influx to alpha(2)M* is blocked by the physiological LRP inhibitor, rec eptor-associated protein. Bivalent antibodies to the extracellular domain o f LRP. but not Fab fragments of the same antibody, cause calcium influx, in dicating that the response is specific to LRP and may require dimerization of the receptor. Thus, LRP is an endocytic receptor with a novel signaling role.