Citation: Yajing Hou, Qifan Yang, Nan Zhou, Li Li, Zhuo Li, Yaning Zhu, Zhiyuan Fang, Tongfei Yang, Peng Zhang, Dezhong Zhou, Delu Che. Cationic modifications in gonadotropin-releasing hormone analogues drive mas-related G protein-coupled receptor X2-dependent histamine release through charge interactions[J]. Chinese Chemical Letters, ;2026, 37(10): 112094. doi: 10.1016/j.cclet.2025.112094 shu

Cationic modifications in gonadotropin-releasing hormone analogues drive mas-related G protein-coupled receptor X2-dependent histamine release through charge interactions

Yajing Hou ^a ,
Qifan Yang ^b ,
Nan Zhou ^a ,
Li Li ^a ,
Zhuo Li ^a ,
Yaning Zhu ^a ,
Zhiyuan Fang ^a ,
Tongfei Yang ^a ,
Peng Zhang ^{a, *,} ,
Dezhong Zhou ^{c, *,} ,
Delu Che ^{d, *,}

a.
Department of Pharmacy, Shaanxi Provincial People’s Hospital, Xi’an 710068, China
b.
Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China
c.
School of Chemical Engineering and Technology, Xi’an Jiaotong University, Xi’an 710049, China
d.
Department of Dermatology, Northwest Hospital, Xi’an Jiaotong University Second Affiliated Hospital, Xi’an 710004, China

m13335383051@163.com

dezhong.zhou@xjtu.edu.cn

chedelu22@163.com

Received Date: 24 July 2025
Revised Date: 6 November 2025
Accepted Date: 7 November 2025
Available Online: 10 November 2025

Figures(4)

Gonadotropin-releasing hormone (GnRH) analogues are widely used polypeptide therapeutics whose clinical utility is limited by pseudo-allergic reactions mediated through histamine release. This study systematically investigated the correlation between GnRH analogue-induced histamine release and the mast cell receptor Mas-related G protein-coupled receptor X2 (MRGPRX2)-a key mediator of drug-induced pseudo-allergic reactions-sing integrated, in vivo, and structural analyses. In vitro experiments demonstrated that GnRH analogues trigger MRGPRX2-dependent Ca²⁺ mobilization and mast cell degranulation, resulting in dose-dependent increases in β-hexosaminidase, histamine, and tumor necrosis factor α (TNF-α) release. Among the analogues tested, nafarelin exhibited the highest potency, whereas buserelin exhibited the lowest. In vivo, these analogues induced mast cell degranulation and capillary dilation in mouse paw skin, leading to localized pseudo-allergic symptoms (edema and extravasation) that were confirmed to be MRGPRX2-mediated. Molecular docking revealed that the cationic amino acid at position eight of the GnRH analogues bound complementarily to the negatively charged center within the MRGPRX2 ligand-binding pocket, suggesting a mechanistic basis for receptor activation. Functional validation via Arg8-to-Glu substitution in triptorelin significantly attenuated MRGPRX2 activation. Collectively, this work elucidates the MRGPRX2-dependent molecular mechanism underlying GnRH analogue-induced histamine release and provides a foundation for designing safer analogues with reduced adverse effects.
- Receptor-ligand interaction,
- Drug structure modification,
- GnRH analogue,
- MRGPRX2,
- Pseudo-allergic reactions
1. [1]
  O. Ortmann, J.M. Weiss, K. Diedrich, Reprod. Biomed. Online 5 (2002) 1–7.
2. [2]
  D. Weckermann, R. Harzmann, Eur. Urol. 46 (2004) 279–284. doi: 10.1016/j.eururo.2004.05.006
3. [3]
  X. Luo, Y. Wu, X. Zhang, et al., Chin. Chem. Lett. 36 (2025) 109724. doi: 10.1016/j.cclet.2024.109724
4. [4]
  C. Gobello, Reprod. Domest. Anim. 47 (2012) 373–376. doi: 10.1111/rda.12025
5. [5]
  S.J. Freedland, P.A. Abrahamsson, Asian J. Androl. 23 (2021) 3–10. doi: 10.4103/aja.aja_22_20
6. [6]
  T. Raja, R. Sud, S. Addla, et al., Indian J. Cancer 59 (2022) S142–S159. doi: 10.4103/ijc.ijc_65_21
7. [7]
  A.P. Metbulut, K.T. Adıgüzel, C. İslamoğlu, et al., Indian J. Endocrinol. Metab. 25 (2021) 527–531. doi: 10.4103/ijem.ijem_333_21
8. [8]
  J.B. Engel, A. Schultze-Mosgau, K. Diedrich, Reprod. Biomed. Online 10 (2005) 61–65. doi: 10.1016/S1472-6483(11)60392-1
9. [9]
  T. Kirkgoz, E. Karakoc-Aydiner, F. Bugrul, et al., Horm. Res. Paediatr. 93 (2020) 66–72. doi: 10.1159/000505329
10. [10]
  J.E. Morgan, C.E. O’Neil, D.H. Coy, et al., Int. Arch. Allergy Appl. Immunol. 80 (1986) 70–75. doi: 10.1159/000234028
11. [11]
  J.J. Nestor Jr, R. Tahilramani, T.L. Ho, et al., J. Med. Chem. 35 (1992) 3942–3948. doi: 10.1021/jm00099a023
12. [12]
  W. Koechling, R. Hjortkjaer, L.B. Tankó, Br. J. Clin. Pharmacol. 70 (2010) 580–587. doi: 10.1111/j.1365-2125.2010.03730.x
13. [13]
  H. Wu, M. Zeng, E.Y. Cho, et al., Prog. Histochem. Cyto. 50 (2015) 11–17. doi: 10.1016/j.proghi.2015.06.001
14. [14]
  B.D. McNeil, P. Pundir, S. Meeker, et al., Nature 519 (2015) 237–241. doi: 10.1038/nature14022
15. [15]
  T. Zhang, D.L. Che, R. Liu, et al., Eur. J. Immunol. 47 (2017) 1949–1958. doi: 10.1002/eji.201746951
16. [16]
  Y.J. Hou, D.L. Che, D. Wei, et al., Mol. Immunol. 111 (2019) 118–127. doi: 10.1016/j.molimm.2019.04.008
17. [17]
  K. Lansu, J. Karpiak, J. Liu, et al., Nat. Chem. Biol. 13 (2017) 529–536. doi: 10.1038/nchembio.2334
18. [18]
  K. Wolf, H. Kühn, F. Boehm, et al., J. Allergy Clin. Immunol. 148 (2021) 506–522. doi: 10.1016/j.jaci.2020.12.655
19. [19]
  H. Subramanian, K. Gupta, H. Ali, J. Allergy Clin. Immunol. 138 (2016) 700–710. doi: 10.1016/j.jaci.2016.04.051
20. [20]
  H. Ali, J. Immunobiol. 1 (2016) 115. doi: 10.1109/IWCI.2016.7860350
21. [21]
  M. Kumar, K. Duraisamy, B.K.C. Chow, Cells 10 (2021) 31. doi: 10.1515/openps-2021-0004
22. [22]
  C. Chompunud Na Ayudhya, S. Roy, I. Alkanfari, et al., Int. J. Mol. Sci. 20 (2019) 5247. doi: 10.3390/ijms20215247
23. [23]
  I. Alkanfari, K. Gupta, T. Jahan, H. Ali, J. Immunol. 201 (2018) 343–349. doi: 10.4049/jimmunol.1701793
24. [24]
  C. Cao, H.J. Kang, I. Singh, et al., Nature 600 (2021) 170–175. doi: 10.1038/s41586-021-04126-6
25. [25]
  F. Yang, L. Guo, Y. Li, et al., Nature 600 (2021) 164–169. doi: 10.1038/s41586-021-04077-y
26. [26]
  S. Roy, A. Ganguly, M. Haque, H. Ali, J. Immunol. 202 (2019) 1229–1238. doi: 10.4049/jimmunol.1801227
27. [27]
  R. Seifert, A. Strasser, E.H. Schneider, et al., Trends Pharmacol. Sci. 34 (2013) 33–58.
28. [28]
  D.P. Green, N. Limjunyawong, N. Gour, et al., Neuron 101 (2019) 412–420. doi: 10.1016/j.neuron.2019.01.012
29. [29]
  H. Kühn, P. Kolkhir, M. Babina, et al., J. Allergy Clin. Immunol. 147 (2020) 456–469.
30. [30]
  A.B. Lüchinger, V. Mijatovic, T. Rustemeyer, P.G. Hompes, Am. J. Med. Sci. 341 (2011) 240–242. doi: 10.1097/MAJ.0b013e31820094da
31. [31]
  W. Zhou, V. Rodic, S. Kitanovic, et al., J. Biol. Chem. 270 (1995) 18853–18857. doi: 10.1074/jbc.270.32.18853
32. [32]
  G. Flouret, K. Mahan, T. Majewski, J. Med. Chem. 35 (1992) 636–640. doi: 10.1021/jm00082a004
33. [33]
  J. Li, J. Chen, Q.L. Hu, et al., Chin. Chem. Lett. 36 (2025) 110126.
34. [34]
  J. Deng, J. Shi, D. Li, J. Zheng, Chin. Chem. Lett. 31 (2020) 2365–2374.
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2. [2]
  Guang Zeng , Yue Zeng , Huamin Hu , Yaqing Bai , Fangjie Nie , Junfei Duan , Zhaoyong Chen , Qi-Long Zhu . Regulating pore structure and pseudo-graphitic phase of hard carbon anode towards enhanced sodium storage performance. Chinese Chemical Letters, 2025, 36(7): 110122-. doi: 10.1016/j.cclet.2024.110122
3. [3]
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7. [7]
  Kun Shang , Yinghua Lv , Yibo Yang , Senyu Yang , Zelong Chen , Ke Yang , Cong Li , Shuang Chao , Yuchao Lu , Yuxin Pei , Zhichao Pei . "Dual sweet" supramolecular glycosyl-nanoproteins based on carbohydrate-protein interaction for targeted drug delivery in vivo. Chinese Chemical Letters, 2026, 37(7): 111798-. doi: 10.1016/j.cclet.2025.111798
8. [8]
  Haiming Wu , Gaya N. Andrew , Rajini Anumula , Zhixun Luo . Corrigendum to 'How ligand coordination and superatomic-states accommodate the structure and property of a metal cluster: Cu₄ (dppy)₄ Cl₂ vs. Cu₂₁ (dppy)₁₀ with altered photoluminescence' [Chin. Chem. Lett. 35 (2024) 108340]. Chinese Chemical Letters, 2024, 35(12): 109912-. doi: 10.1016/j.cclet.2024.109912
9. [9]
  Ziyi Liu , Xunying Liu , Lubing Qin , Haozheng Chen , Ruikai Li , Zhenghua Tang . Alkynyl ligand for preparing atomically precise metal nanoclusters: Structure enrichment, property regulation, and functionality enhancement. Chinese Journal of Structural Chemistry, 2024, 43(11): 100405-100405. doi: 10.1016/j.cjsc.2024.100405
10. [10]
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11. [11]
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12. [12]
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15. [15]
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16. [16]
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