ABNORMAL DEPHOSPHORYLATION EFFECT ON NMDA RECEPTOR REGULATION IN ALS SPINAL-CORD

Previous studies have demonstrated a significant reduction of N-methyl -D-aspartate (NMDA) receptor binding in spinal cord sections from pati ents who died with amyotrophic lateral sclerosis (ALS) compared to tha t in control patients. The reduction in NMDA receptor binding In ALS c ould be increased toward control values by treatment with phorbol este r, suggesting a role for receptor protein phosphorylation in this diso rder. In the present study we have evaluated the time course of recove ry of [H-3]MK-801 binding following phorbol ester treatment to assess protein phosphatase activity in spinal cord sections from ALS and cont rol subjects. Phorbol ester-stimulated changes in [H-3]MK-801 binding returned to untreated values significantly faster in ALS tissue compar ed to control and could not be blocked by the coapplication of the pro tein phosphatase inhibitors sodium vanadate or sodium beta-D-glycerol phosphate. Okadaic acid coapplication blocked recovery in both ALS and control tissue at a concentration range at which phosphatase 2B (calc ineurin) would likely be inhibited. The results suggest that abnormal levels or activity of protein phosphatases, including calcineurin, may be involved in the abnormal levels of NMDA receptors in ALS and may p lay some role in the pathogenesis of the disease. (C) 1997 Academic Pr ess.