Identification and characterization of compounds that potentiate NT-3-mediated Trk receptor activity.
Neurotrophins are a family of secreted proteins that play an important role in the development, differentiation, and survival of neurons. Studies also suggest that aberrant neurotrophin signaling may play a role in processes underlying disease states such as schizophrenia, Alzheimer's disease, and depression. Whereas the development of agents that selectively stimulate neurotrophin signaling has proven to be difficult, compounds have been identified that potentiate neurotrophin 3 (NT-3)-mediated activation of trk A. In the present studies, we extend those initial observations to identify compounds that also potentiate NT-3-mediated activation of trk B. Compound potentiation of NT-3 was observed using several readouts of transfected and endogenous trk receptor activity, including trk receptor phosphorylation, mitogen-activated protein kinase phosphorylation, reporter assay activity (beta-lactamase and luciferase), cell survival and neurite extension assays. Studies using chimeric trk receptors demonstrated that the extracellular domain is essential for compound potentiation and rule out interaction with intracellular signaling molecules as a mechanism of compound activity. Thus, the present studies demonstrate that trk B receptor activity can be potentiated by small-molecule compounds via the extracellular domain of the receptor and provide reagents for further evaluating the role of NT-3-mediated trk A and trk B activity in vivo.
Lewis
Martin A
MA
3CD-499, Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Hunihan
Lisa
L
Franco
Diana
D
Robertson
Barbara
B
Palmer
Jane
J
Laurent
Denis R St
DR
Balasubramanian
Balu N
BN
Li
Yi
Y
Westphal
Ryan S
RS
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D018076:DNA, Complementary; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020933:Neurotrophin 3 / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D020813:Receptor, trkB / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D018076:DNA, Complementary; D020933:Neurotrophin 3; D020813:Receptor, trkB; D020928:Mitogen-Activated Protein Kinases