A possible role for tyrosine kinases in the regulation of the neuronal dopamine transporter in mouse striatum.
The present investigation was undertaken to test the hypothesis that a reduction in the activity of protein tyrosine kinases would result in an alteration in dopamine transport. Genistein, a broad-spectrum inhibitor of protein tyrosine kinases, inhibited dopamine uptake into mouse striatal homogenates with an IC50 of 18 microM. The inhibition by genistein was rapid, reversible and somewhat selective, in that genistein did not inhibit the uptake of choline or GABA under similar conditions. Kinetic analyses indicated that genistein was a non-competitive inhibitor. Another protein tyrosine kinase inhibitor, tyrphostin 23, also inhibited transport but was significantly less potent than genistein. Tyrphostin 25 and lavendustin A were without major effect on dopamine uptake. In addition, the inactive structural analog of genistein, genistein, had no significant effect on dopamine uptake. The inhibition of dopamine transport by 50 microM genistein was accompanied by a reduction in the level of a 110-kDa band of tyrosine phosphoprotein. It is suggested that protein tyrosine kinases play a role in the cascade of events which ultimately lead to regulation of neuronal dopamine transport.
Simon
J R
JR
Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA. jsimon@indyvax.iupui.edu
Bare
D J
DJ
Ghetti
B
B
Richter
J A
JA
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology*; D014793:Visual Cortex / Q000187:drug effects*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D007529:Isoflavones; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019833:Genistein; D011505:Protein-Tyrosine Kinases