Secreted amyloid precursor protein α selectively suppresses N-methyl-d-aspartate currents in hippocampal neurons: involvement of cyclic GMP

Abstract

The secreted form of β-amyloid precursor protein (sAPPα) is released from neurons in an activity-dependent manner; data suggest sAPPα may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPPα can suppress elevation of [Ca2+]i induced by glutamate and can protect neurons against excitotoxicity. We now report whole-cell patch-clamp data from studies of cultured embryonic rat hippocampal neurons which demonstrate sAPPα selectively suppresses N-methyl-d-aspartate currents without affecting currents induced by α-amino-3-hydroxy-5-methylisoxazole-4-propionate or kainate. sAPPα suppressed N-methyl-d-aspartate current rapidly and reversibly at concentrations of 0.01–1nM. Suppression of N-methyl-d-aspartate current by sAPPα is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppressed N-methyl-d-aspartate current in a manner similar to sAPPα, and two different inhibitors of cyclic guanosine monophosphate-dependent protein kinase prevented sAPPα-induced suppression of N-methyl-d-aspartate current. In addition, okadaic acid prevented suppression of N-methyl-d-aspartate-induced current suggesting the involvement of a protein phosphatase in modulation of N-methyl-d-aspartate current by sAPPα.These data identify a mechanism whereby sAPPα can modulate cellular responses to glutamate, and suggest important roles for sAPPα in the various physiological and pathophysiological processes in which N-methyl-d-aspartate receptors participate.