KATP通道与偏头痛的相关研究进展
Research Progress on the Relationship between KATP Channels and Migraine
DOI: 10.12677/acm.2026.1682811, PDF,   
作者: 欧阳思绮：西北民族大学医学部，甘肃 兰州；万东君*：联勤保障部队第九四零医院神经内科，甘肃 兰州
关键词: 偏头痛；ATP敏感性钾通道；发病机制；三叉神经血管系统；治疗靶点；Migraine； ATP-Sensitive Potassium Channels； Pathogenesis； Trigeminovascular System； Therapeutic Targets
摘要: 偏头痛是全球高发的致残性神经系统疾病，发病机制涵盖神经血管激活、皮质扩散性、神经源性炎症、代谢紊乱及离子通道异常等多维度调控异常，现有曲普坦类、CGRP靶向药物仍存在部分患者应答不足、耐受性差等局限。ATP敏感性钾通道(KATP通道)作为细胞能量代谢核心传感器，可动态调控血管张力、神经元兴奋性及三叉神经血管系统活化，其功能异常与偏头痛启动、维持密切相关。本文系统梳理KATP通道分子结构、组织分布及生理病理功能，重点阐述其介导偏头痛发生的核心通路、临床与临床前证据，总结靶向KATP通道的抗偏头痛治疗研发进展，现存挑战与未来方向，为偏头痛机制阐述及新型靶点药物开发提供理论支撑。
Abstract: Migraine is a worldwide prevalent disabling neurological disorder with complex pathogenesis involving neurovascular activation, cortical spreading depression, neurogenic inflammation, metabolic disturbance and ion channel abnormalities. Current therapies including triptans and CGRP-targeted agents still have limitations such as insufficient response and poor tolerance in some patients. ATP-sensitive potassium [KATP] channels, as core sensors of cellular energy metabolism, can dynamically regulate vascular tone, neuronal excitability and trigeminovascular system activation, and their dysfunction is closely related to migraine initiation and maintenance. This review systematically summarizes the molecular structure, tissue distribution, physiological and pathological functions of KATP channels, focuses on the core pathways mediating migraine, clinical and preclinical evidence, and summarizes the research progress, existing challenges and future directions of anti-migraine therapy targeting KATP channels, so as to provide theoretical support for elucidating migraine mechanism and developing novel targeted drugs.
文章引用：欧阳思绮, 万东君. KATP通道与偏头痛的相关研究进展[J]. 临床医学进展, 2026, 16(8): 427-434. https://doi.org/10.12677/acm.2026.1682811

参考文献

[1] Ashina, M., Buse, D.C., Ashina, H., Pozo-Rosich, P., Peres, M.F.P., Lee, M.J., et al. (2021) Migraine: Integrated Approaches to Clinical Management and Emerging Treatments. The Lancet, 397, 1505-1518.
https://doi.org/10.1016/s0140-6736(20)32342-4
[2] Dong, L., Dong, W., Jin, Y., Jiang, Y., Li, Z. and Yu, D. (2025) The Global Burden of Migraine: A 30-Year Trend Review and Future Projections by Age, Sex, Country, and Region. Pain and Therapy, 14, 297-315.
https://doi.org/10.1007/s40122-024-00690-7
[3] 韩雅婷, 郭淮莲. 偏头痛的代谢组学研究进展[J]. 中国疼痛医学杂志, 2021, 27(9): 682-687.
[4] 陈艳, 李俊青, 郭路, 等. 皮质扩布抑制在偏头痛中的作用机制及治疗策略研究进展[J]. 中国疼痛医学杂志, 2026, 32(3): 207-214.
[5] 徐菲, 刘儒昶, 王天云, 等. 偏头痛的遗传学研究进展[J]. 中国疼痛医学杂志, 2024, 30(1): 52-56.
[6] Christensen, R.H., Ashina, H. and Ashina, M. (2025) The Vessel-to-Neuron Trigeminovascular Hypothesis of Migraine Pathogenesis—The “Pro” Argument. The Journal of Headache and Pain, 26, Article No. 248.
https://doi.org/10.1186/s10194-025-02130-z
[7] Morgan, C.T. and Nkadimeng, S.M. (2025) The Role of Inflammation in Migraine Headaches: A Review. FASEB BioAdvances, 7, e70033.
https://doi.org/10.1096/fba.2024-00188
[8] Chiang, C., Porreca, F., Robertson, C.E. and Dodick, D.W. (2024) Potential Treatment Targets for Migraine: Emerging Options and Future Prospects. The Lancet Neurology, 23, 313-324.
https://doi.org/10.1016/s1474-4422(24)00003-6
[9] Kuburas, A. and Russo, A.F. (2023) Shared and Independent Roles of CGRP and PACAP in Migraine Pathophysiology. The Journal of Headache and Pain, 24, Article No. 34.
https://doi.org/10.1186/s10194-023-01569-2
[10] Clement, A., Guo, S., Jansen-Olesen, I. and Christensen, S.L. (2022) ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential. Cells, 11, Article No. 2406.
https://doi.org/10.3390/cells11152406
[11] Al-Karagholi, M.A., Hansen, J.M., Guo, S., Olesen, J. and Ashina, M. (2019) Opening of ATP-Sensitive Potassium Channels Causes Migraine Attacks: A New Target for the Treatment of Migraine. Brain, 142, 2644-2654.
https://doi.org/10.1093/brain/awz199
[12] Gross, E.C., Lisicki, M., Fischer, D., Sándor, P.S. and Schoenen, J. (2019) The Metabolic Face of Migraine—From Pathophysiology to Treatment. Nature Reviews Neurology, 15, 627-643.
https://doi.org/10.1038/s41582-019-0255-4
[13] Al-Karagholi, M.A., Hansen, J.M., Severinsen, J., Jansen-Olesen, I. and Ashina, M. (2017) The KATP Channel in Migraine Pathophysiology: A Novel Therapeutic Target for Migraine. The Journal of Headache and Pain, 18, Article No. 90.
https://doi.org/10.1186/s10194-017-0800-8
[14] Ashina, M., Terwindt, G.M., Al-Karagholi, M.A., de Boer, I., Lee, M.J., Hay, D.L., et al. (2021) Migraine: Disease Characterisation, Biomarkers, and Precision Medicine. The Lancet, 397, 1496-1504.
https://doi.org/10.1016/s0140-6736(20)32162-0
[15] Ding, D., Wu, J., Duan, X., Ma, S., Lai, L. and Chen, L. (2022) Structural Identification of Vasodilator Binding Sites on the SUR2 Subunit. Nature Communications, 13, Article No. 2675.
https://doi.org/10.1038/s41467-022-30428-y
[16] McClenaghan, C. and Nichols, C.G. (2022) Kir6.1 and SUR2B in Cantú Syndrome. American Journal of Physiology-Cell Physiology, 323, C920-C935.
https://doi.org/10.1152/ajpcell.00154.2022
[17] Daoud, H.A.S., Kokoti, L. and Al-Karagholi, M.A. (2024) KATP Channels in Cerebral Hemodynamics: A Systematic Review of Preclinical and Clinical Studies. Frontiers in Neurology, 15, Article ID: 1417421.
https://doi.org/10.3389/fneur.2024.1417421
[18] Wang, M., Wu, J., Ding, D. and Chen, L. (2022) Structural Insights into the Mechanism of Pancreatic KATP Channel Regulation by Nucleotides. Nature Communications, 13, Article No. 2770.
https://doi.org/10.1038/s41467-022-30430-4
[19] Lv, J., Xiao, X., Bi, M., Tang, T., Kong, D., Diao, M., et al. (2022) ATP-Sensitive Potassium Channels: A Double-Edged Sword in Neurodegenerative Diseases. Ageing Research Reviews, 80, Article ID: 101676.
https://doi.org/10.1016/j.arr.2022.101676
[20] Ando, K., Tong, L., Peng, D., Vázquez-Liébanas, E., Chiyoda, H., He, L., et al. (2022) KCNJ8/ABCC9-Containing K-ATP Channel Modulates Brain Vascular Smooth Muscle Development and Neurovascular Coupling. Developmental Cell, 57, 1383-1399.e7.
https://doi.org/10.1016/j.devcel.2022.04.019
[21] Ashcroft, F.M. and Rorsman, P. (2013) KATP Channels and Islet Hormone Secretion: New Insights and Controversies. Nature Reviews Endocrinology, 9, 660-669.
https://doi.org/10.1038/nrendo.2013.166
[22] Gundi, B., Ho, H.L., Zhang, X., He, A., Xin, D., Ferreira, A.F.F., et al. (2026) Therapeutic Potential of KATP Channels in the Attenuation of Parkinson's Disease Pathogenesis and Progression—A Review. Neurochemistry International, 192, Article ID: 106091.
https://doi.org/10.1016/j.neuint.2025.106091
[23] Nelson, P.T., Estus, S., Abner, E.L., Parikh, I., Malik, M., Neltner, J.H., et al. (2014) ABCC9 Gene Polymorphism Is Associated with Hippocampal Sclerosis of Aging Pathology. Acta Neuropathologica, 127, 825-843.
https://doi.org/10.1007/s00401-014-1282-2
[24] Aguilera, P., Alquisiras-Burgos, I., Franco-Pérez, J. and Rubio-Osornio, M. (2022) The Short Form of the SUR1 and Its Functional Implications in the Damaged Brain. Neural Regeneration Research, 17, 488-496.
https://doi.org/10.4103/1673-5374.320967
[25] Jha, R.M., Rani, A., Desai, S.M., Raikwar, S., Mihaljevic, S., Munoz-Casabella, A., et al. (2021) Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review. International Journal of Molecular Sciences, 22, Article No. 11899.
https://doi.org/10.3390/ijms222111899
[26] Ashcroft, F.M. (2007) ATP-Sensitive K+ Channels and Disease: From Molecule to Malady. American Journal of Physiology-Endocrinology and Metabolism, 293, E880-E889.
https://doi.org/10.1152/ajpendo.00348.2007
[27] Díaz-Pérez, A., de Eulate, N.A., Masvidal-Codina, E., Illa, X., Navarro, X., Guimerà-Brunet, A., et al. (2026) Cortical Spreading Depolarizations in Stroke: Mechanisms, Neuroprotective Interventions, and Monitoring Techniques. GeroScience, 48, 2123-2151.
https://doi.org/10.1007/s11357-025-01988-w
[28] Christiansen, I., Thomsen, L., Daugaard, D., Ulrich, V. and Olesen, J. (1999) Glyceryl Trinitrate Induces Attacks of Migraine without Aura in Sufferers of Migraine with Aura. Cephalalgia, 19, 660-667.
https://doi.org/10.1046/j.1468-2982.1999.019007660.x
[29] Al-Karagholi, M.A., Ghanizada, H., Nielsen, C.A.W., Hougaard, A. and Ashina, M. (2021) Opening of ATP Sensitive Potassium Channels Causes Migraine Attacks with Aura. Brain, 144, 2322-2332.
https://doi.org/10.1093/brain/awab136
[30] Zhao, J. and Levy, D. (2018) Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset. The Journal of Neuroscience, 38, 5053-5066.
https://doi.org/10.1523/jneurosci.0115-18.2018
[31] Kokoti, L., Al-Karagholi, M.A. and Ashina, M. (2020) Latest Insights into the Pathophysiology of Migraine: The ATP-Sensitive Potassium Channels. Current Pain and Headache Reports, 24, Article No. 77.
https://doi.org/10.1007/s11916-020-00911-6
[32] Charles, A. and Pozo-Rosich, P. (2019) Targeting Calcitonin Gene-Related Peptide: A New Era in Migraine Therapy. The Lancet, 394, 1765-1774.
https://doi.org/10.1016/s0140-6736(19)32504-8
[33] Christensen, S.L., Munro, G., Petersen, S., Shabir, A., Jansen-Olesen, I., Kristensen, D.M., et al. (2020) ATP Sensitive Potassium (KATP) Channel Inhibition: A Promising New Drug Target for Migraine. Cephalalgia, 40, 650-664.
https://doi.org/10.1177/0333102420925513
[34] Messlinger, K. and Russo, A.F. (2019) Current Understanding of Trigeminal Ganglion Structure and Function in Headache. Cephalalgia, 39, 1661-1674.
https://doi.org/10.1177/0333102418786261
[35] Szeto, V., Chen, N.H., Sun, H.S. and Feng, Z.P. (2018) The Role of KATP Channels in Cerebral Ischemic Stroke and Diabetes. Acta Pharmacologica Sinica, 39, 683-694.
https://doi.org/10.1038/aps.2018.10
[36] Liao, C.C., Liao, K.R. and Li, J.M. (2026) Unraveling the Cross-Tissue Neuroimmune-Vascular Genetic Architecture of Migraine Using Integrated Multi-Omics, Single-Cell, and Spatial Transcriptomics: Prioritizing T-Cell Regulatory Networks and Peripheral Targets. International Journal of Molecular Sciences, 27, Article No. 1615.
https://doi.org/10.3390/ijms27031615
[37] Clement, A., Christensen, S.L., Jansen-Olesen, I., Olesen, J. and Guo, S. (2023) The ATP Sensitive Potassium Channel (KATP) Is a Novel Target for Migraine Drug Development. Frontiers in Molecular Neuroscience, 16, Article ID: 1182515.
https://doi.org/10.3389/fnmol.2023.1182515
[38] Russo, A.F. and Hay, D.L. (2023) CGRP Physiology, Pharmacology, and Therapeutic Targets: Migraine and Beyond. Physiological Reviews, 103, 1565-1644.
https://doi.org/10.1152/physrev.00059.2021
[39] Kokoti, L., Al-Karagholi, M.A., Zhuang, Z.A., Amirguliyev, S., Amin, F.M. and Ashina, M. (2024) Non-Vascular ATP-Sensitive Potassium Channel Activation Does Not Trigger Migraine Attacks: A Randomized Clinical Trial. Cephalalgia, 44.
https://doi.org/10.1177/03331024241248211
[40] Li, K., McClenahan, S.J., Han, C., Bungard, J.D., Rathnayake, U., Boutaud, O., et al. (2024) Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KATP Channels. Molecular Pharmacology, 105, 202-212.
https://doi.org/10.1124/molpharm.123.000783
[41] Raffaelli, B., Do, T.P., Chaudhry, B.A., Amin, F.M., Ashina, H., Snellman, J., et al. (2024) Activation of ATP-Sensitive Potassium Channels Triggers Migraine Attacks Independent of Calcitonin Gene-Related Peptide Receptors: A Randomized Placebo-Controlled Trial. Cephalalgia, 44.
https://doi.org/10.1177/03331024231222916
[42] Christensen, S.L., Rasmussen, R.H., Cour, S.L., Ernstsen, C., Hansen, T.F., Kogelman, L.J., et al. (2022) Smooth Muscle ATP-Sensitive Potassium Channels Mediate Migraine-Relevant Hypersensitivity in Mouse Models. Cephalalgia, 42, 93-107.
https://doi.org/10.1177/03331024211053570
[43] Christophersen, P. and Dyhring, T. (2023) The Shortcoming of Using Glibenclamide in Exploratory Clinical Headache Provocation Studies. Cephalalgia, 43.
https://doi.org/10.1177/03331024231219475
[44] Kokoti, L., Al-Karagholi, M.A., Waldorff Nielsen, C.A. and Ashina, M. (2023) Glibenclamide Posttreatment Does Not Inhibit Levcromakalim Induced Headache in Healthy Participants: A Randomized Clinical Trial. Neurotherapeutics, 20, 389-398.
https://doi.org/10.1007/s13311-023-01350-y
[45] Al-Karagholi, M.A., Ghanizada, H., Kokoti, L., Paulsen, J.S., Hansen, J.M. and Ashina, M. (2020) Effect of KATP Channel Blocker Glibenclamide on Levcromakalim-Induced Headache. Cephalalgia, 40, 1045-1054.
https://doi.org/10.1177/0333102420949863
[46] Thomsen, A.V., Al-Karagholi, M.A., Hougaard, A., Ostrowski, S.R., Pedersen, O.B., Hansen, T.F., et al. (2024) Investigations of the Migraine-Provoking Effect of Levcromakalim in Patients with Migraine with Aura. Cephalalgia, 44.
https://doi.org/10.1177/03331024241237247
[47] Dyhring, T., Jansen-Olesen, I., Christophersen, P. and Olesen, J. (2023) Pharmacological Profiling of KATP Channel Modulators: An Outlook for New Treatment Opportunities for Migraine. Pharmaceuticals, 16, Article No. 225.
https://doi.org/10.3390/ph16020225
[48] Chen, P.Y., Yen, J.C., Liu, T.T., et al. (2023) Neuronal NLRP3 Inflammasome Mediates Spreading Depolarization-Evoked Trigeminovascular Activation. Brain, 146, 2989-3002.
https://doi.org/10.1093/brain/awad045

为你推荐