Activation of Trk receptors and their main post-receptor signaling pathways by dipeptide mimetics of NGF, BDNF, and NT-3

Parent neurotrophinCodeNeurotrophin loopConcentration (M)Trk receptor activationActivation of post-receptor signaling cascades
PI3K/AktMAPK/ERKPLC-γ1
NGFGK-2 [37, 41]410–8TrkA++ns++
GK-6 [37, 41]110–6TrkA+++
GTS-115 [34, 41]310–6TrkA++++
BDNFGSB-106 [38, 41]410–8TrkB+++++
GSB-214 [38, 41]110–7TrkB+ns++
GTS-201 [35, 41]210–7TrkBns+++
NT-3GTS-301 [33, 42]410–6TrkCns++++
GTS-302 [36, 42]10–6TrkC+++++

Full-length NGF, BDNF and NT-3 at concentrations of 10–9 M were used as positive controls. Trk: tyrosine kinase; NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; NT-3: neurotrophin-3; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinase; PLC-γ1: phospholipase C-gamma; GK-2: bis-(monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide; GK-6: bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide; GSB-106: bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide; GSB-214: bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide; GTS-115: bis-(N-gamma-oxybutyryl-L-lysyl-L-histidine) hexamethylenediamide; GTS-201: bis-(N-hexanoyl-L-seryl-L-lysine) hexamethylenediamide; GTS-301: bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) hexamethylenediamide; GTS-302: bis-(N-gamma-oxybutyryl-L-glutamyl-L-asparagine) hexamethylenediamide; +: the effect is inferior to the full-length neurotrophin in terms of intensity and/or duration; ++: the effect is comparable to the full-length neurotrophin in terms of intensity and duration; ns: non-significant