Extrasynaptic NMDA receptor

Hilmar Bading and colleagues uncovered that extrasynaptic NMDA receptors form a signaling complex with the transient receptor potential cation channel subfamily M member 4 (TRPM4).[1] The NMDAR/TRPM4 complex is considered central to glutamate excitotoxicity.[1] NMDAR/TRPM4 interaction interface inhibitors (also known as 'TwinF interface inhibitors') disrupt the NMDAR/TRPM4 complex thereby detoxifying extrasynaptic NMDA receptors.[1] In mouse disease models, TwinF interface inhibitors protect against stroke induced brain damage,[1][2] retinal ganglion cell degeneration,[3] amyotrophic lateral sclerosis (ALS),[4] Huntington's disease,[5] Alzheimer's disease,[6] and demonstrate antidepressant efficacy in treatment-resistant depression.[7]

References

  1. 1 2 3 4 Yan, Jing; Bengtson, C. Peter; Buchthal, Bettina; Hagenston, Anna M.; Bading, Hilmar (9 October 2020). "Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants". Science. 370 (6513) eaay3302. doi:10.1126/science.aay3302. PMID 33033186.
  2. ↑ Sun, Meiling; Wang, Lin; Cao, Qiaofeng; Wang, Xuechun; Zhang, Ying; Guo, Manyu; Chen, Jie; Ma, Yuchen; Niu, Le; Zhang, Yanping; Hu, Mengdie; Gu, Mengli; Zhu, Zhihui; Yao, Xinyi; Yao, Junchen; Zhao, Chen; Wu, Jin; Liu, Xiuxiu; Lu, Yingmei; Wang, Zhen; Xiang, Qiuping; Han, Feng; Zhu, Dongsheng (23 January 2025). "Discovery of HZS60 as a Novel Brain Penetrant NMDAR/TRPM4 Interaction Interface Inhibitor with Improved Activity and Pharmacokinetic Properties for the Treatment of Cerebral Ischemia". Journal of Medicinal Chemistry. 68 (2): 2008–2043. doi:10.1021/acs.jmedchem.4c02772. PMID 39745498.
  3. ↑ Wang, Yu Meng; Yan, Jing; Williams, Sarah K.; Fairless, Richard; Bading, Hilmar (12 September 2024). "TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis". Acta Neuropathologica Communications. 12 (1) 149. doi:10.1186/s40478-024-01858-0. PMC 11391826. PMID 39267142.
  4. ↑ Yan, Jing; Wang, Yu Meng; Hellwig, Andrea; Bading, Hilmar (February 2024). "TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS". Cell Reports Medicine. 5 (2) 101413. doi:10.1016/j.xcrm.2024.101413. PMC 10897598. PMID 38325382.
  5. ↑ Oberländer, Kristin; Pruunsild, Priit; Koch, Philipp; Yan, Jing; Szafranski, Karol; Bading, Hilmar (3 December 2025). "Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling". Communications Biology. 8 (1) 1743. doi:10.1038/s42003-025-09074-9. PMC 12678830. PMID 41339520.
  6. ↑ Yan, Jing; Yang, Xiaohui; Li, Guilin; Ramirez, Omar A.; Hagenston, Anna M.; Chen, Zhe-Yu; Bading, Hilmar (February 2026). "The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease". Molecular Psychiatry. 31 (2): 635–648. doi:10.1038/s41380-025-03143-5. PMC 12815682. PMID 40858778.
  7. ↑ Beher, Dirk; Yan, Jing (17 March 2026). "Why NMDA receptor modulation remains central to next-generation depression therapies". Drug Target Review.
This page is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.