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 patients who died with amyotrophic lateral sclerosis (ALS) compared to that in control patients. The reduction in NMDA receptor binding in ALS could be increased toward control values by treatment with phorbol ester, suggesting a role for receptor protein phosphorylation in this disorder. In the present study we have evaluated the time course of recovery of [3H]MK-801 binding following phorbol ester treatment to assess protein phosphatase activity in spinal cord sections from ALS and control subjects. Phorbol ester-stimulated changes in [3H]MK-801 binding returned to untreated values significantly faster in ALS tissue compared to control and could not be blocked by the coapplication of the protein 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 (calcineurin) 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 play some role in the pathogenesis of the disease.
Wagey
R
R
Department of Medicine, University of British Columbia, Vancouver, Canada.
Krieger
C
C
Shaw
C A
CA
D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D019319:Okadaic Acid / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D014316:Tritium
D002273:Carcinogens; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010703:Phorbol Esters; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D019319:Okadaic Acid; D016291:Dizocilpine Maleate; D010744:Phosphoric Monoester Hydrolases