Activation of NMDA receptors and Ca2+/calmodulin-dependent protein kinase participate in phosphorylation of neurofilaments induced by protein kinase C.
Aberrant phosphorylation of neurofilaments, similar to that occurring in various motor neuron diseases, is produced in cultured motor neurons by activation of protein kinase C (PKC). Following exposure to synthetic diacylglycerol, persistent change in the phosphorylation state of C-terminal domains of neurofilament proteins was detected by increased perikaryal immunoreactivity with the antibody SMI34; this antibody recognizes NF-M/NF-H when C-terminal KSP repeat domains are highly phosphorylated. SMI34 labeling of perikarya and dendrites was prevented by pretreatment with either the NMDA receptor antagonist APV or by the Ca2+/calmodulin-dependent protein kinase (CaMK) inhibitor KN-62, but not by antagonists of AMPA/kainate or metabotropic glutamate receptors or by inhibitors of arachidonic acid metabolic pathways. Thus, activation of PKC may induce neurofilament phosphorylation in motor neurons by acting in cooperation with stimulation of NMDA receptors and activation of CaMK. These mechanisms may be relevant to motor neuron disease and other neuronal injuries in which increased PKC activity has been measured.
Doroudchi
M M
MM
Montreal Neurological Institute and Department of Neurology/Neurosurgery, McGill University, Quebec, Canada.
Durham
H D
HD
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051379:Mice; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D016900:Neurofilament Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016718:Arachidonic Acid; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases