2. Academic Validation
  3. Chelerythrine inhibits NR2B NMDA receptor independent of PKC activity

Chelerythrine inhibits NR2B NMDA receptor independent of PKC activity

  • Biochem Biophys Res Commun. 2024 Dec 20:739:150914. doi: 10.1016/j.bbrc.2024.150914.
Jie Hao 1,  Xia Qin 1,  LiZhao Guan 2,  Siruan Chen 1,  Xuenan Hao 1,  Panpan Zhang 1,  Hui Bai 3,  Wenya Zhao 1,  Zhuo Huang 4,  Shifeng Chu 5,  Haishui Shi 6,  Zhanfeng Jia 7,  Zuxiao Yang 8,  Dezhi Kong 9,  Wei Zhang 10
Affiliations

Affiliations

  • 1 Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China.
  • 2 ICE BIOSCIENCE INC, 101,floor, 1,Building, 16 Yard, 18 Kechuang 13th Street, Daxing District, Beijing, China.
  • 3 Department of Cardiac Ultrasound, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
  • 4 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 5 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 6 Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang, 050017, China.
  • 7 Department of Pharmacology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang, 050017, China.
  • 8 Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China. Electronic address: yangzuxiao@hebmu.edu.cn.
  • 9 Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China. Electronic address: kongdezhi@hebmu.edu.cn.
  • 10 Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China. Electronic address: weizhang@hebmu.edu.cn.
PMID: 39536412 DOI: 10.1016/j.bbrc.2024.150914
Abstract

N-methyl-d-aspartate receptors (NMDARs), the ligand ion glutamate receptor channels, mediate major excitatory neurotransmission in central nervous system (CNS). They highly express in CNS and involve in multiple physiological processes. Many studies implicated that NMDAR plays a crucial role in number of neurological disorders, including ischemia, dementia, and pain, indicating its potential as a therapeutic target for treatments. Chelerythrine (CHE) is a benzo-phenanthridine alkaloid extracted from Chelidonium majus with many biological activities including anti-inflammatory, Anticancer effect, and antidiabetic effect. But the mechanism of CHE is not well understood. The aim of this study was to investigate the effect of CHE on the NMDAR. The results demonstrated that CHE effectively suppressed NMDA-induced currents in primary cultured cortical neurons. To elucidate the underlying mechanism, we expressed NMDARs in HEK293T cells and found that CHE and some of its structural analogues inhibited NMDAR currents and facilitated the desensitization of GluN2B NMDARs. Notably, these effects were independent of protein kinase C activity, suggesting that the effect of CHE on GluN2B-containing NMDAR may occur through a mechanism of directly interaction with NMDAR. Moreover, the inhibitory effect of CHE on GluN2B NMDARs is pH-dependent. Molecular docking prediction in conjunction with mutagenesis analysis revealed that the M3 α-helical segment of the NMDAR in close proximity to the GluN2B Thr647 amino acid plays an important role in CHE inhibition of GluN2B. This study revealed a novel function of CHE and its structural analogues in inhibiting the NMDARs and promoting GluN2B-mediated desensitization by obstructing the receptor at the channel pore region.

Keywords

Chelerythrine; Desensitization; NMDARs.

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