Neuronal responses to myelin are mediated by rho kinase.
CNS myelin inhibits axon growth due to the expression of several growth-inhibitory proteins, including myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein and Nogo. Myelin-associated inhibitory proteins activate rho GTPase in responsive neurons. Rho kinase (ROCK) has been implicated as a critical rho effector in this pathway due to the ability of the pharmacological inhibitor Y-27632 to circumvent myelin-dependent inhibition. Y-27632, however, inhibits the activity of additional kinases. Using three independent approaches, we provide direct evidence that ROCKII is activated in response to the myelin-associated inhibitor Nogo. We demonstrate that Nogo treatment enhances ROCKII translocation to the cellular membrane in PC12 cells and enhances ROCKII kinase activity towards an in vitro substrate. In addition, Nogo treatment enhances phosphorylation of myosin light chain II, a known ROCK substrate. Further, we demonstrate that primary dorsal root ganglia neurons can be rendered insensitive to the inhibitory effects of myelin via infection with dominant negative ROCK. Together these data provide direct evidence for a rho-ROCK-myosin light chain-II signaling cascade in response to myelin-associated inhibitors.
Alabed
Yazan Z
YZ
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, Canada.
Grados-Munro
Edith
E
Ferraro
Gino B
GB
Hsieh
Sidney H-K
SH
Fournier
Alyson E
AE
D000577:Amides / Q000494:pharmacology; D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D009185:Myelin Proteins / Q000378:metabolism* / Q000494:pharmacology; D018994:Myosin Light Chains / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology; D009420:Nervous System / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D000070798:Nogo Proteins; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009185:Myelin Proteins; D018994:Myosin Light Chains; D000070798:Nogo Proteins; D011725:Pyridines; C000603197:Rtn4 protein, rat; C107184:myosin light chain 2; C108830:Y 27632; C061570:protein kinase N; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D024722:Cardiac Myosins; D020741:rho GTP-Binding Proteins