K-252b selectively potentiates cellular actions and trk tyrosine phosphorylation mediated by neurotrophin-3.
K-252b, a protein kinase inhibitor, has been shown earlier to inhibit nerve growth factor actions on cholinergic neurons of the basal forebrain. In the present study, K-252b was found to prevent trophic actions of two other neurotrophins, brain-derived neurotrophic factor, and neurotrophin-3, on central cholinergic and dopaminergic neurons, peripheral sensory neurons, and PC12 pheochromocytoma cells, when used at greater than 2 microM concentration. Comparable actions of nonneurotrophin growth factors were not affected. Surprisingly, at 0.1-100 nM, K-252b selectively enhanced the trophic action of neurotrophin-3 on central cholinergic neurons, peripheral sensory neurons, and PC12 cells. In PC12 cells, K-252b potentiated the neurotrophin-3-induced tyrosine phosphorylation of trk, a protein kinase responsible for transmitting neurotrophin signals. Of the three structurally related nerve growth factor inhibitors, K-252a, K-252b, and staurosporine, only the first two also mediated neurotrophin-3 potentiation. These findings indicate that K-252b generally and selectively potentiates the neurotrophic action of neurotrophin-3 and suggest that this action involves trk-type neurotrophin receptors.
Knüsel
B
B
Department of Biological Sciences, University of Southern California, Los Angeles 90089.
Kaplan
D R
DR
Winslow
J W
JW
Rosenthal
A
A
Burton
L E
LE
Beck
K D
KD
Rabin
S
S
Nikolics
K
K
Hefti
F
F
D000310:Adrenal Gland Neoplasms / Q000378:metabolism / Q000473:pathology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D026121:Indole Alkaloids; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3; D010673:Pheochromocytoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000032:analysis / Q000378:metabolism*
D000470:Alkaloids; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; C049985:staurosporine aglycone; D020917:Receptor, trkA; D011493:Protein Kinase C; D019311:Staurosporine