Targeting Supramolecular Active Complexes of Na v 1.7/Na v 1.8 to Relieve Chronic Neuropathic Pain
Source abstract
Abstract
ABSTRACT Neuropathic pain (NP) affects 7%–10% of population, with current treatments often proving inadequate. Here we show that Na v 1.7 and Na v 1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Na v 1.7/Na v 1.8 SMACs. Targeting these SMACs with combined Na v 1.7 and Na v 1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na + potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.
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Research context
OpenAlex topics: Pain Mechanisms and Treatments · Nerve injury and regeneration · Neuropeptides and Animal Physiology
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
The First Rehabilitation Hospital of Shanghai Brain and Spinal Cord Innovation Research Center Translational Research Institute of Brain and Brain‐Like Intelligence，Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Clinical Research Center For Anesthesiology and Perioperative Medicine School of Medicine Tongji University Shanghai China
Department of Neurobiology School of Basic Medicine Fourth Military Medical University Xi'an China
Department of Orthopedics Xijing Hospital Fourth Military Medical University Xi'an China
Xiang‐Xing College Hunan University of Traditional Chinese Medicine Changsha China
Pre‐clinical College Dali University Dali Yunnan China
Department of Anesthesiology and Perioperative medicine Shanghai Fourth People's Hospital Shanghai China
The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation Xi'an China
Funding
National Natural Science Foundation of China
References (100+)
Show source-provided references
1. 10.1016/j.pain.2013.11.01310.1016/j.pain.2013.11.013 ↗
2. 10.1016/j.pain.2007.08.01310.1016/j.pain.2007.08.013 ↗
3. 10.1016/S1474‐4422(14)70251‐010.1016/S1474‐4422(14)70251‐0 ↗
4. 10.1074/jbc.272.23.1480510.1074/jbc.272.23.14805 ↗
5. 10.1006/geno.1996.044710.1006/geno.1996.0447 ↗
6. 10.1007/s00335990023510.1007/s003359900235 ↗
7. 10.1152/physrev.00052.201710.1152/physrev.00052.2017 ↗
8. 10.1038/379257a010.1038/379257a0 ↗
9. 10.1074/jbc.271.11.595310.1074/jbc.271.11.5953 ↗
10. 10.1523/JNEUROSCI.2695‐04.200410.1523/JNEUROSCI.2695‐04.2004 ↗
11. 10.1002/ana.2248510.1002/ana.22485 ↗
12. 10.1136/jmg.2003.01215310.1136/jmg.2003.012153 ↗
13. 10.1073/pnas.121608010910.1073/pnas.1216080109 ↗
14. 10.1177/174480691666608310.1177/1744806916666083 ↗
15. 10.1523/JNEUROSCI.2710‐13.201310.1523/JNEUROSCI.2710‐13.2013 ↗
16. 10.1124/mol.118.11307610.1124/mol.118.113076 ↗
17. 10.1073/pnas.040491510110.1073/pnas.0404915101 ↗
18. 10.1038/ncomms179510.1038/ncomms1795 ↗
19. 10.1038/nature0541310.1038/nature05413 ↗
20. 10.1038/919510.1038/9195 ↗
21. 10.1523/JNEUROSCI.22‐19‐08352.200210.1523/JNEUROSCI.22‐19‐08352.2002 ↗
22. 10.1097/j.pain.000000000000122710.1097/j.pain.0000000000001227 ↗
23. 10.2174/138955751566615072211262110.2174/1389557515666150722112621 ↗
24. 10.1002/advs.20240543210.1002/advs.202405432 ↗
25. 10.1038/289322a010.1038/289322a0 ↗
26. 10.1038/2576410.1038/25764 ↗
27. 10.1038/3001810.1038/30018 ↗
28. 10.3390/cells1102027210.3390/cells11020272 ↗
29. 10.1038/ni83610.1038/ni836 ↗
30. 10.1073/pnas.04260179910.1073/pnas.042601799 ↗
31. 10.1186/s12990‐015‐0065‐710.1186/s12990‐015‐0065‐7 ↗
32. 10.1085/jgp.20241359610.1085/jgp.202413596 ↗
33. 10.1101/2022.11.05.2228192910.1101/2022.11.05.22281929 ↗
34. 10.1016/j.pneurobio.2021.10202410.1016/j.pneurobio.2021.102024 ↗
35. 10.1038/nn.388110.1038/nn.3881 ↗
36. 10.1038/s41467‐021‐21725‐z10.1038/s41467‐021‐21725‐z ↗
37. 10.1038/s41593‐024‐01794‐110.1038/s41593‐024‐01794‐1 ↗
38. 10.1038/s41467‐018‐04049‐310.1038/s41467‐018‐04049‐3 ↗
39. 10.1126/science.aam767110.1126/science.aam7671 ↗
40. 10.1016/j.cell.2014.11.03810.1016/j.cell.2014.11.038 ↗
41. 10.1242/dev.16561310.1242/dev.165613 ↗
42. 10.3389/fncel.2019.0027110.3389/fncel.2019.00271 ↗
43. 10.1016/j.bmc.2018.12.00210.1016/j.bmc.2018.12.002 ↗
44. 10.1111/j.1744‐7348.1939.tb06990.x10.1111/j.1744‐7348.1939.tb06990.x ↗
45. 10.1021/acsmedchemlett.5b0005910.1021/acsmedchemlett.5b00059 ↗
46. 10.1073/pnas.171370111510.1073/pnas.1713701115 ↗
47. 10.1016/j.nmd.2006.02.00510.1016/j.nmd.2006.02.005 ↗
48. 10.1111/j.1529‐8027.2012.00443.x10.1111/j.1529‐8027.2012.00443.x ↗
49. 10.1038/s41596‐024‐01011‐010.1038/s41596‐024‐01011‐0 ↗
50. 10.1093/bib/bbs01610.1093/bib/bbs016 ↗
51. 10.1128/mcb.9.11.4835‐4845.198910.1128/mcb.9.11.4835‐4845.1989 ↗
52. 10.1093/nar/gkac90710.1093/nar/gkac907 ↗
53. 10.1038/nrn340410.1038/nrn3404 ↗
54. 10.1016/j.cell.2019.11.00410.1016/j.cell.2019.11.004 ↗
55. 10.1007/978-1-4614-1533-6_24210.1007/978-1-4614-1533-6_242 ↗
56. 10.1016/B0-72-160797-7/50101-410.1016/B0-72-160797-7/50101-4 ↗
57. 10.1186/1744‐8069‐7‐3210.1186/1744‐8069‐7‐32 ↗
58. 10.1038/nature0997510.1038/nature09975 ↗
59. 10.1523/jneurosci.3424‐06.200610.1523/jneurosci.3424‐06.2006 ↗
60. 10.1016/j.celrep.2023.11231510.1016/j.celrep.2023.112315 ↗
61. 10.1186/s12990‐015‐0057‐710.1186/s12990‐015‐0057‐7 ↗
62. 10.1016/j.neulet.2021.13608710.1016/j.neulet.2021.136087 ↗
63. 10.1523/jneurosci.22‐23‐10277.200210.1523/jneurosci.22‐23‐10277.2002 ↗
64. 10.1152/jn.2001.86.2.62910.1152/jn.2001.86.2.629 ↗
65. 10.1016/j.celrep.2013.12.03310.1016/j.celrep.2013.12.033 ↗
66. 10.1093/brain/awab08610.1093/brain/awab086 ↗
67. 10.2174/138945012066619013111424410.2174/1389450120666190131114244 ↗
68. 10.1186/1744‐8069‐8‐8210.1186/1744‐8069‐8‐82 ↗
69. 10.1016/j.neuron.2020.07.02610.1016/j.neuron.2020.07.026 ↗
70. 10.1113/jphysiol.2003.04212710.1113/jphysiol.2003.042127 ↗
71. 10.1016/j.pain.2012.04.02210.1016/j.pain.2012.04.022 ↗
72. 10.4161/chan.2244510.4161/chan.22445 ↗
73. 10.1152/jn.2000.84.2.71010.1152/jn.2000.84.2.710 ↗
74. 10.1016/s0304‐3959(99)00251‐110.1016/s0304‐3959(99)00251‐1 ↗
75. 10.7554/eLife.2323510.7554/eLife.23235 ↗
76. 10.1073/pnas.250357012210.1073/pnas.2503570122 ↗
77. 10.1007/s12264‐017‐0132‐310.1007/s12264‐017‐0132‐3 ↗
78. 10.1523/jneurosci.5746‐12.201310.1523/jneurosci.5746‐12.2013 ↗
79. 10.1158/0008‐5472.can‐03‐094610.1158/0008‐5472.can‐03‐0946 ↗
80. 10.1523/jneurosci.21‐16‐06077.200110.1523/jneurosci.21‐16‐06077.2001 ↗
81. 10.1371/journal.pone.015240510.1371/journal.pone.0152405 ↗
82. 10.1016/j.bmcl.2014.06.03810.1016/j.bmcl.2014.06.038 ↗
83. 10.1016/j.pain.2013.06.02210.1016/j.pain.2013.06.022 ↗
84. 10.1523/jneurosci.3649‐04.200410.1523/jneurosci.3649‐04.2004 ↗
85. 10.1523/jneurosci.2068‐05.200510.1523/jneurosci.2068‐05.2005 ↗
86. 10.1038/s41586‐025‐09896‐x10.1038/s41586‐025‐09896‐x ↗
87. 10.1172/jci17353710.1172/jci173537 ↗
88. 10.1080/19336950.2023.228925610.1080/19336950.2023.2289256 ↗
89. 10.1016/j.bja.2018.01.01610.1016/j.bja.2018.01.016 ↗
90. 10.3389/fnmol.2023.109109610.3389/fnmol.2023.1091096 ↗
91. 10.1038/nbt.411510.1038/nbt.4115 ↗
92. 10.1038/s41587‐021‐01092‐210.1038/s41587‐021‐01092‐2 ↗
93. 10.1038/nmeth.208910.1038/nmeth.2089 ↗
94. 10.1038/nmeth.201910.1038/nmeth.2019 ↗
95. 10.1038/nbt.151110.1038/nbt.1511 ↗
96. 10.1093/nar/gkab103810.1093/nar/gkab1038 ↗
97. 10.1038/s41586‐024‐07487‐w10.1038/s41586‐024‐07487‐w ↗
98. 10.1371/journal.pbio.100128310.1371/journal.pbio.1001283 ↗
99. 10.3390/ijms1901016110.3390/ijms19010161 ↗
100. 10.1371/journal.pone.001868110.1371/journal.pone.0018681 ↗