Brain-derived neurotrophic factor–Tropomyosin receptor kinase B signaling system (BDNF-TrkB) (BDNF-TrkB)

The Brain-derived neurotrophic factor (BDNF)–Tropomyosin receptor kinase B (TrkB) signaling system is a central regulator of neuronal survival, growth, and synaptic plasticity [1, 2]. BDNF, a member of the neurotrophin family, binds with high affinity to the TrkB receptor, a transmembrane receptor tyrosine kinase encoded by the NTRK2 gene [6, 9]. Upon ligand binding, TrkB undergoes dimerization and autophosphorylation, which activates downstream signaling cascades including the PI3K/Akt, MAPK/ERK, and PLCγ pathways [1, 7]. These pathways are critical for long-term potentiation, the cellular mechanism underlying learning and memory, and for the maintenance of healthy neural circuits [3, 8]. Dysregulation of BDNF-TrkB signaling is implicated in a wide range of conditions, such as major depressive disorder, Alzheimer's disease, Parkinson's disease, and obesity [3, 6, 12]. Recent research has demonstrated that various antidepressants and psychedelics act as positive allosteric modulators by binding directly to the TrkB transmembrane domain to enhance BDNF signaling [2, 4, 5]. In oncology, NTRK2 gene fusions or TrkB overexpression can drive the progression of certain tumors, making the receptor a target for small-molecule kinase inhibitors [1, 4]. Therapeutic development focuses on TrkB agonists for neuroprotection and Trk inhibitors for cancer, though challenges include achieving blood-brain barrier penetration and receptor specificity [1, 7].

Other names

BDNF-NTRK2 signalingNeurotrophin-4/5-TrkB signalingBDNF-TrkB pathwayBDNF-TrkB-CREB signaling pathway

Activation of the TrkB receptor by its ligand BDNF leads to receptor dimerization and autophosphorylation of intracellular tyrosine residues, which recruits adaptor proteins to initiate the PI3K/Akt, MAPK/ERK, and PLCγ signaling pathways [1, 6]. These cascades promote neuronal survival, dendritic branching, and synaptic strengthening [7, 9]. Recent evidence indicates that antidepressants and psychedelics can bind directly to the TrkB transmembrane domain, acting as positive allosteric modulators that facilitate BDNF-induced signaling and promote neural plasticity [2, 4, 5].