journal article·2025-10Open access

Structural Basis of GABA B Receptor Activation during Evolution

Guofei Hou, Shenglan Zhang, Cangsong Shen, Suyu Ji, Binqian Zou, Chanjuan Xu, Liang Li, Dandan Shen, Jiayin Liang, Haidi Chen, Philippe Rondard, Cheng Deng, Jun He, Yan Zhang, Jianfeng Liu

Advanced Science· Volume 12· Issue 37

Abstract

Abstract GABA B receptor is a Class C G protein‐coupled receptor (GPCR) for γ‐aminobutyric acid (GABA), the principal inhibitory neurotransmitter. It forms an obligatory heterodimer consisting of two subunits, GB1 and GB2. Whether the activation mechanism of the GABA B receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo‐EM) structures of the drosophila GABA B receptor in both antagonist‐bound inactive state and GABA‐bound active state in complex with G i protein are reported. The drosophila GABA B receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABA B receptor constitutive activity. Four key residues, which are not conserved in drosophila GABA B receptor, are responsible for the activity of the positive allosteric modulator in its human homolog. Whereas the intracellular loop 2 of drosophila GB2 (dGB2) is less involved, the ordered C terminus of dGB2 and its corresponding region in its human homolog are required for G protein coupling. These evolutionary variations provide a complete understanding of the activation mechanism of the GABA B receptor and new insights for future development of allosteric modulators for medication and insecticides.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Receptor Mechanisms and Signaling · Neuroscience and Neuropharmacology Research · Nicotinic Acetylcholine Receptors Study

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Cellular Signaling laboratory International Research Center for Sensory Biology and Technology of MOST Key Laboratory of Molecular Biophysics of MOE School of Life Science and Technology Huazhong University of Science and Technology Wuhan 430074 China

Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) Guangzhou 510005 China

Hubei Jiangxia Laboratory Wuhan Hubei 430200 China

Department of Biophysics and Department of Pathology of Sir Run Shaw Hospital Zhejiang University School of Medicine Hangzhou 310058 China

CAS Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine GIBH‐HKU Guangdong‐Hong Kong Stem Cell and Regenerative Medicine Research Centre GIBH‐CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou 510530 China

Department of Respiratory and Critical Care Medicine Center for High Altitude Medicine Institutes for Systems Genetics National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu 610213 China

Institut de Génomique Fonctionnelle Univ. Montpellier CNRS INSERM Montpellier 34094 France

Liangzhu Laboratory Zhejiang University Hangzhou 311121 China

Center for Structural Pharmacology and Therapeutics Development Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou 310016 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Ministry of Science and Technology

References (88)

Show source-provided references
1. 10.2183/pjab.94.02610.2183/pjab.94.026 ↗
2. 10.1007/7854_2020_12910.1007/7854_2020_129 ↗
3. 10.1523/JNEUROSCI.18-05-01913.199810.1523/JNEUROSCI.18-05-01913.1998 ↗
4. 10.1523/JNEUROSCI.16-20-06374.199610.1523/JNEUROSCI.16-20-06374.1996 ↗
5. 10.1038/nrn324910.1038/nrn3249 ↗
6. 10.1152/physrev.00036.200310.1152/physrev.00036.2003 ↗
7. 10.1124/pr.54.2.24710.1124/pr.54.2.247 ↗
8. 10.1038/npp.2011.30010.1038/npp.2011.300 ↗
9. 10.1002/ana.2503210.1002/ana.25032 ↗
10. 10.1002/ana.2515510.1002/ana.25155 ↗
11. 10.1016/j.msard.2018.10.00910.1016/j.msard.2018.10.009 ↗
12. 10.3389/fnins.2014.0014010.3389/fnins.2014.00140 ↗
13. 10.1016/j.neuropharm.2016.04.02810.1016/j.neuropharm.2016.04.028 ↗
14. 10.7554/eLife.7018810.7554/eLife.70188 ↗
15. 10.1042/BJ2015097910.1042/BJ20150979 ↗
16. 10.1021/ml500162z10.1021/ml500162z ↗
17. 10.1146/annurev.pharmtox.011008.14553310.1146/annurev.pharmtox.011008.145533 ↗
18. 10.1016/j.pharmthera.2011.01.00610.1016/j.pharmthera.2011.01.006 ↗
19. 10.1038/2536010.1038/25360 ↗
20. 10.1016/S0896-6273(00)00012-X10.1016/S0896-6273(00)00012-X ↗
21. 10.1093/emboj/20.9.215210.1093/emboj/20.9.2152 ↗
22. 10.1016/S0026-895X(24)12657-010.1016/S0026-895X(24)12657-0 ↗
23. 10.1038/nature1272510.1038/nature12725 ↗
24. 10.1073/pnas.25155449810.1073/pnas.251554498 ↗
25. 10.1124/mol.62.2.34310.1124/mol.62.2.343 ↗
26. 10.1074/jbc.M10890020010.1074/jbc.M108900200 ↗
27. 10.1038/s41467-019-10834-510.1038/s41467-019-10834-5 ↗
28. 10.1038/s41422-020-0350-510.1038/s41422-020-0350-5 ↗
29. 10.1038/s41586-021-03507-110.1038/s41586-021-03507-1 ↗
30. 10.1038/s41586-020-2408-410.1038/s41586-020-2408-4 ↗
31. 10.1038/s41586-020-2469-410.1038/s41586-020-2469-4 ↗
32. 10.1111/j.1460-9568.2009.06636.x10.1111/j.1460-9568.2009.06636.x ↗
33. 10.1074/jbc.273.41.2636110.1074/jbc.273.41.26361 ↗
34. 10.1523/JNEUROSCI.21-04-01189.200110.1523/JNEUROSCI.21-04-01189.2001 ↗
35. 10.1073/pnas.140008111110.1073/pnas.1400081111 ↗
36. 10.1021/bi991018t10.1021/bi991018t ↗
37. 10.1126/science.283.5398.7410.1126/science.283.5398.74 ↗
38. 10.1038/2535410.1038/25354 ↗
39. 10.1523/JNEUROSCI.21-04-01203.200110.1523/JNEUROSCI.21-04-01203.2001 ↗
40. 10.1046/j.1460-9568.2001.01410.x10.1046/j.1460-9568.2001.01410.x ↗
41. 10.1016/j.neuropharm.2014.08.02210.1016/j.neuropharm.2014.08.022 ↗
42. 10.1038/s41559-020-01338-310.1038/s41559-020-01338-3 ↗
43. 10.1523/JNEUROSCI.0378-08.200810.1523/JNEUROSCI.0378-08.2008 ↗
44. 10.1002/jez.65710.1002/jez.657 ↗
45. 10.1038/s41419-018-0704-910.1038/s41419-018-0704-9 ↗
46. 10.1007/978-1-4684-5907-4_3610.1007/978-1-4684-5907-4_36 ↗
47. 10.1007/s12311-008-0047-710.1007/s12311-008-0047-7 ↗
48. 10.1007/s00359-017-1168-610.1007/s00359-017-1168-6 ↗
49. 10.1038/ncomms982810.1038/ncomms9828 ↗
50. 10.1126/sciadv.adc923610.1126/sciadv.adc9236 ↗
51. 10.1016/S0065-2660(09)65004-510.1016/S0065-2660(09)65004-5 ↗
52. 10.1002/neu.2018410.1002/neu.20184 ↗
53. 10.1242/jeb.08556310.1242/jeb.085563 ↗
54. 10.1016/j.devbrainres.2005.06.00510.1016/j.devbrainres.2005.06.005 ↗
55. 10.1016/S1054-3589(10)58017-710.1016/S1054-3589(10)58017-7 ↗
56. 10.1096/fj.202001355RR10.1096/fj.202001355RR ↗
57. 10.1038/s41467-021-27147-110.1038/s41467-021-27147-1 ↗
58. 10.1126/science.124948910.1126/science.1249489 ↗
59. 10.1038/s41586-020-2452-010.1038/s41586-020-2452-0 ↗
60. 10.1074/jbc.271.4.219910.1074/jbc.271.4.2199 ↗
61. 10.1074/jbc.M10687620010.1074/jbc.M106876200 ↗
62. 10.1038/s41586-024-07055-210.1038/s41586-024-07055-2 ↗
63. 10.1038/s41586-021-03680-310.1038/s41586-021-03680-3 ↗
64. 10.1126/scisignal.abf165310.1126/scisignal.abf1653 ↗
65. 10.1074/jbc.C10019820010.1074/jbc.C100198200 ↗
66. 10.1074/jbc.M10119720010.1074/jbc.M101197200 ↗
67. 10.1038/s41586-021-03819-210.1038/s41586-021-03819-2 ↗
68. 10.1038/s41467-024-46177-z10.1038/s41467-024-46177-z ↗
69. 10.1038/s41586-025-08811-810.1038/s41586-025-08811-8 ↗
70. 10.1038/s41586-021-03691-010.1038/s41586-021-03691-0 ↗
71. 10.1073/pnas.192223111710.1073/pnas.1922231117 ↗
72. 10.1038/s41422-023-00892-210.1038/s41422-023-00892-2 ↗
73. 10.1038/s41586-019-0881-410.1038/s41586-019-0881-4 ↗
74. 10.1038/s41586-021-03641-w10.1038/s41586-021-03641-w ↗
75. 10.1038/s41422-022-00623-z10.1038/s41422-022-00623-z ↗
76. 10.1038/nchembio.171110.1038/nchembio.1711 ↗
77. 10.1038/s41422-023-00830-210.1038/s41422-023-00830-2 ↗
78. 10.1038/s41586-021-03495-210.1038/s41586-021-03495-2 ↗
79. 10.1016/j.jmb.2020.09.02310.1016/j.jmb.2020.09.023 ↗
80. 10.1038/s41467-024-54681-510.1038/s41467-024-54681-5 ↗
81. 10.1038/nprot.2014.17310.1038/nprot.2014.173 ↗
82. 10.1016/S0021-9258(18)41623-710.1016/S0021-9258(18)41623-7 ↗
83. 10.1038/s41586-018-0219-710.1038/s41586-018-0219-7 ↗
84. 10.1016/j.jsb.2005.07.00710.1016/j.jsb.2005.07.007 ↗
85. 10.1038/nmeth.416910.1038/nmeth.4169 ↗
86. 10.1016/j.jsb.2021.10770210.1016/j.jsb.2021.107702 ↗
87. 10.1016/bs.mie.2016.04.01210.1016/bs.mie.2016.04.012 ↗
88. 10.1016/j.cell.2020.01.00710.1016/j.cell.2020.01.007 ↗