首页|Targeting TrkB-PSD-95 coupling to mitigate neurological disorders
Targeting TrkB-PSD-95 coupling to mitigate neurological disorders
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Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cy-Ca2+/calmodulin-dependent protein kinase Ⅱ and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.
Angelman syndromeautismbrain-derived neurotrophic factordepressionneurodegenerative disorderneurodevelopmental disorderpostsynaptic density protein-95synaptic plasticityTrkB
Xin Yang、Yu-Wen Alvin Huang、John Marshall
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Department of Molecular Biology,Cell Biology and Biochemistry,Brown University,Providence,RI,USA
Department of Neurology,Warren Alpert Medical School of Brown University,Providence,RI,USA
Center for Translational Neuroscience,Robert J.and Nancy D.Carney Institute for Brain Science and Brown Institute for Translational Science,Brown University,Providence,RI,USA
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