Stimulation of protein-tyrosine phosphorylation in rat striatum after lesion of dopamine neurons or chronic neuroleptic treatment.
Even though the short-term actions of dopamine on postsynaptic receptors are well-characterized, the molecular bases for long-term trophic interactions between dopamine neurons and their targets remain unclear. Since protein-tyrosine phosphorylation plays a key role in the action of trophic factors, we have investigated its possible involvement in the interactions between dopamine neurons and their striatal targets. Lesioning rat nigrostriatal dopamine neurons by using 6-hydroxydopamine increased the phosphorylation on tyrosine of several proteins, including a major 180-kDa protein (pp180) in the ipsilateral striatum. Protein-tyrosine kinase activity was also increased in the striatum ipsilateral to the lesion, whereas no change in phosphotyrosine phosphatase activity was detected. The stimulation of pp180 phosphorylation was observed 1, 2, and 8 weeks after 6-hydroxydopamine lesion, was selective for the destruction of dopamine neurons, and was mimicked by chronic blockade of dopamine receptors with neuroleptics. Additional lesion experiments and subcellular fractionation showed that pp180 is located in neuronal postsynaptic densities, suggesting that pp180 is a postsynaptic component of corticostriatal synapses. Our results indicate that lesion of specific afferent fibers can activate tyrosine phosphorylation in central neurons and suggest that tyrosine phosphorylation is involved in the long-term consequences of dopamine deficiency and may play a role in synaptic plasticity.
Institut National de la Santé et de la Recherche Médicale U 114, Chaire de Neuropharmacologie, Collège de France, Paris.
J A
JA
Girault
J C
JC
Siciliano
L
L
Robel
D
D
Hervé
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001479:Basal Ganglia / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000502:physiology*; D008297:Male; D008970:Molecular Weight; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013378:Substantia Nigra / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D019000:Phosphotyrosine; D014443:Tyrosine; D016627:Oxidopamine; D011505:Protein-Tyrosine Kinases; D004298:Dopamine