Activation of PKC reverses apparent NMDA receptor reduction in ALS.
The binding of [3H]MK-801 to NMDA receptors was reduced by 40-45% in the dorsal and ventral horns of spinal cords from patients who died with amyotrophic lateral sclerosis (ALS) compared with controls. These results reflect either neurone death with concomitant receptor loss or regulation-related receptor decreases independent of motoneurone degeneration. To distinguish between these possibilities we explored aspects of NMDA receptor regulation using phorbol ester to activate protein kinase C (PKC). Spinal cord sections were exposed to phorbol ester before incubation with [3H]MK-801 to determine levels of NMDA binding. Phorbol ester treatment increased [3H]MK-801 binding in both ALS and control tissue to almost identical levels of specific binding for both groups. The increased [3H]MK-801 binding could be completely blocked by concurrent exposure of spinal cord sections to H-7, a general protein kinase inhibitor. These results suggest that NMDA receptors in ALS spinal cord are decreased as a result of abnormal enzyme activity independent of motoneurone degeneration.
Krieger
C
C
Department of Medicine, University of British Columbia, University Hospital, Vancouver, Canada.
Wagey
R
R
Lanius
R A
RA
Shaw
C A
CA
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000378:metabolism*; D001345:Autoradiography; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D007546:Isoquinolines; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D015240:Phorbol 12,13-Dibutyrate; D016291:Dizocilpine Maleate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C