Modification of NMDA receptor by in vitro lipid peroxidation in fetal guinea pig brain

Abstract

The effect of lipid peroxidation on the NMDA receptor and its modulatory sites in fetal guinea pig brain cell membranes was examined. P2 membrane fractions were prepared from the fetal brain tissue and peroxidized in the presence of ferric chloride and ascorbate. [ 3H]-MK-801-binding studies were performed and B max (number of binding sites) and Kd (affinity) values were used as indices of NMDA receptor modification. In lipid-peroxidized membranes the Kd value increased from 6.76 ± 2.69 in control to 15.12 ± 7.38 nM ( P<0.01), indicating a decreased affinity of NMDA receptors following lipid peroxidation. However, there was no significant change in B max. The glutamate- and glycine-dependent increase in activation was 40% lower in lipid-peroxidized membranes as compared to control. The spermine-dependent activation was also significantly reduced following lipid peroxidation as compared to control suggesting decreased affinity of spermine site. The results of this study indicate that lipid peroxidation modifies recognition, coactivator and spermine sites of NMDA receptor by decreasing its affinity without affecting the number of binding sites. Normal activation of NMDA receptor is important for neuritic growth, synaptogenesis, long-term potentiation and synaptic plasticity. Therefore, we speculate that any clinical condition causing lipid peroxidation of brain cell membranes could jeopardize these maturational processes in the developing brain causing neurological impairment.