Systems Pharmacology of the NGF Signaling Through p75 and TrkA Receptors
نویسندگان
چکیده
The nerve growth factor (NGF) pathway has been shown to play a key role in pain treatment. Recently, a systems pharmacology model has been proposed that can aid in the identification and validation of drug targets in the NGF pathway. However, this model did not include the role of the p75 receptor, which modulates the signaling of NGF through the tropomyosin receptor kinase A (TrkA). The precise mechanism of the interaction between these two receptors has not been completely elucidated, and we therefore adopted a systems pharmacology modeling approach to gain understanding of the effect of p75 on the dynamics of NGF signal transduction. Specifically, models were developed for the so-called heterodimer and for the ligand-passing hypotheses. We used the model to compare the effect of inhibition of NGF and TrkA and its implication for drug discovery and development for pain treatment.
منابع مشابه
The extracellular domain of p75NTR is necessary to inhibit neurotrophin-3 signaling through TrkA.
The TrkA receptor is activated primarily by nerve growth factor (NGF), but it can also be activated by high concentrations of neurotrophin 3 (NT-3). The pan-neurotrophin receptor p75(NTR) strongly inhibits activation of TrkA by NT-3 but not by NGF. To examine the role of p75(NTR) in regulating the specificity of TrkA signaling, we expressed both receptors in Xenopus oocytes. Application of NGF ...
متن کاملp75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity in protection from enediyne chemotherapeutic agents.
Growth factors, including nerve growth factor (NGF), have been hypothesized to play a role in resistance to chemotherapeutic agent-induced apoptosis. Induction by NGF of resistance to apoptosis is primarily thought to be the result of its binding to its high-affinity receptor, TrkA. The low-affinity NGF receptor, p75, has long been thought merely to facilitate NGF binding to TrkA. However, we h...
متن کاملStructural and Mechanistic Insights into Nerve Growth Factor Interactions with the TrkA and p75 Receptors
Nerve growth factor engages two structurally distinct transmembrane receptors, TrkA and p75, which have been proposed to create a "high-affinity" NGF binding site through formation of a ternary TrkA/NGF/p75 complex. To define a structural basis for the high-affinity site, we have determined the three-dimensional structure of a complete extracellular domain of TrkA complexed with NGF. The comple...
متن کاملOptimal nerve growth factor trophic signals mediated by synergy of TrkA and p75 receptor-specific ligands.
Nerve growth factor (NGF) receptor-mediated signaling was studied using specific monoclonal antibodies (mAbs) as ligands that discriminate between the receptors TrkA and p75. mAb-induced trophic signals were compared with the signals of the natural ligand NGF. In cells expressing TrkA but no p75 receptors (TrkA+ p75(-)), binding of TrkA with mAb 5C3 leads to optimal signals. In cells expressing...
متن کاملp75 and TrkA signaling regulates sympathetic neuronal firing patterns via differential modulation of voltage-gated currents.
Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) act through the tropomyosin-related receptor tyrosine kinases (Trk) and the pan-neurotrophin receptor (p75) to regulate complex developmental and functional properties of neurons. While NGF activates both receptor types in sympathetic neurons, differential signaling through TrkA and p75 can result in wi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 3 شماره
صفحات -
تاریخ انتشار 2014