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The non‐peptidyl fungal metabolite L‐783,281 activates TRK neurotrophin receptors
Author(s) -
Wilkie Neil,
Wingrove Peter B.,
Bilsland James G.,
Young Lisa,
Harper Sarah J.,
Hefti Franz,
Ellis Semantha,
Pollack Scott J.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00504.x
Subject(s) - trk receptor , neurotrophin , tropomyosin receptor kinase a , neurite , receptor , biology , low affinity nerve growth factor receptor , microbiology and biotechnology , phosphorylation , receptor tyrosine kinase , biochemistry , chemistry , in vitro
Neurotrophin binding to the extracellular surface of the Trk family of tyrosine kinase receptors leads to the activation of multiple signalling cascades, culminating in neuroregenerative effects, including neuronal survival and neurite outgrowth. Since neurotrophins themselves are not ideal drug candidates due to their poor pharmacokinetic behaviour and bioavailability, small molecule neurotrophin mimetics may be beneficial in treating a number of neurodegenerative disorders. The present study demonstrates that L‐783,281, a non‐peptidyl fungal metabolite, is capable of stimulating Trk A, B and C phosphorylation to various extents in CHO cells stably expressing human Trk receptors. L‐783,281 also stimulated Trk phosphorylation in a number of rat and human primary neuronal cultures, whereas the highly similar compound, L‐767,827, was without effect. Mechanistic studies utilizing transiently transfected PDGF/ Trk A and Trk A/PDGF chimeras, demonstrated that L‐783,281 is likely to interact with the intracellular domain of the Trk A receptor. Further investigations suggested that L‐783,281 was nevertheless able to instigate receptor dimerization by binding in a non‐covalent manner. Although the cytotoxicity of the compound was shown to preclude its effects in neuronal survival and neurite outgrowth assays, it is a prototype for a small molecule neurotrophin mimetic that activates Trk by interacting at a site different from the neurotrophin‐binding site.