TrkB transmembrane domain: bridging structural understanding with therapeutic strategy

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2024-05, Vol.49 (5), p.445-456
• Main Authors: Enkavi, Giray, Girych, Mykhailo, Moliner, Rafael, Vattulainen, Ilpo, Castrén, Eero
• Format: Article
• Language: English
• Subjects: allosteric modulators; Animals; antidepressant drugs; Antidepressive Agents - chemistry; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Brain-Derived Neurotrophic Factor - chemistry; Brain-Derived Neurotrophic Factor - metabolism; cholesterol; Humans; Membrane Glycoproteins; neuroplasticity; neurotrophic factors; Protein Domains; psychedelics; Receptor, trkB - chemistry; Receptor, trkB - metabolism; Signal Transduction
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2024.02.001

The dimer of the neuronal receptor tyrosine kinase-2 (TrkB) transmembrane domains (TMDs) is a novel target for drug binding.Antidepressant drugs act as allosteric potentiators of brain-derived neurotrophic factor (BDNF) signaling through binding to TrkB.Cholesterol modulates the structure and function of TrkB.Agonist TrkB antibodies are being developed for neurodegenerative disorders. TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the receptor for brain-derived neurotrophic factor (BDNF) and is a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding of the structure and function of TrkB, including its transmembrane domain (TMD). TrkB interacts with membrane cholesterol, which bidirectionally regulates TrkB signaling. Additionally, TrkB has recently been recognized as a binding target of antidepressant drugs. A variety of different antidepressants, including typical and rapid-acting antidepressants, as well as psychedelic compounds, act as allosteric potentiators of BDNF signaling through TrkB. This suggests that TrkB is the common target of different antidepressant compounds. Although more research is needed, current knowledge suggests that TrkB is a promising target for further drug development. TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the receptor for brain-derived neurotrophic factor (BDNF) and is a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding of the structure and function of TrkB, including its transmembrane domain (TMD). TrkB interacts with membrane cholesterol, which bidirectionally regulates TrkB signaling. Additionally, TrkB has recently been recognized as a binding target of antidepressant drugs. A variety of different antidepressants, including typical and rapid-acting antidepressants, as well as psychedelic compounds, act as allosteric potentiators of BDNF signaling through TrkB. This suggests that TrkB is the common target of different antidepressant compounds. Although more research is needed, current knowledge suggests that TrkB is a promising target for further drug development.