电压门控钾通道作为治疗靶点。
Voltage-gated potassium channels as therapeutic targets.
作者信息
Wulff Heike, Castle Neil A, Pardo Luis A
机构信息
Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, GBSF Room 3502, Davis, California 95616, USA.
出版信息
Nat Rev Drug Discov. 2009 Dec;8(12):982-1001. doi: 10.1038/nrd2983.
Abstract
The human genome encodes 40 voltage-gated K(+) channels (K(V)), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca(2+) signalling and cell volume, to driving cellular proliferation and migration. K(V) channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting K(V) channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the K(V)1 subfamily, the K(V)7 subfamily (also known as KCNQ), K(V)10.1 (also known as EAG1 and KCNH1) and K(V)11.1 (also known as HERG and KCNH2) channels.
摘要
人类基因组编码40种电压门控钾离子通道（K(V)），这些通道参与多种生理过程，从神经元和心脏动作电位的复极化，到调节Ca(2+)信号传导和细胞体积，再到驱动细胞增殖和迁移。K(V)通道为开发治疗癌症、自身免疫性疾病以及代谢、神经和心血管疾病的新药提供了巨大机遇。本综述讨论了用毒液肽、抗体和小分子靶向K(V)通道的药理学策略，并重点介绍了靶向K(V)1亚家族、K(V)7亚家族（也称为KCNQ）、K(V)10.1（也称为EAG1和KCNH1）和K(V)11.1（也称为HERG和KCNH2）通道的药物在临床前和临床开发方面的最新进展。
相似文献
1
Voltage-gated potassium channels as therapeutic targets.电压门控钾通道作为治疗靶点。
Nat Rev Drug Discov. 2009 Dec;8(12):982-1001. doi: 10.1038/nrd2983.
2
Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy.电压门控钾通道的药理学调节作为一种治疗策略。
Expert Opin Ther Pat. 2010 Nov;20(11):1471-503. doi: 10.1517/13543776.2010.513384. Epub 2010 Aug 20.
3
Voltage-Gated K Channel Modulation by Marine Toxins: Pharmacological Innovations and Therapeutic Opportunities.电压门控钾通道的海洋毒素调制：药理学创新与治疗机会。
Mar Drugs. 2024 Jul 29;22(8):350. doi: 10.3390/md22080350.
4
Venom-derived peptide inhibitors of voltage-gated potassium channels.毒液来源的电压门控钾通道肽抑制剂。
Neuropharmacology. 2017 Dec;127:124-138. doi: 10.1016/j.neuropharm.2017.07.002. Epub 2017 Jul 5.
5
A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties.一种具有 Kunitz 型蛋白酶和钾通道抑制特性的多功能海葵肽。
Biochem Pharmacol. 2011 Jul 1;82(1):81-90. doi: 10.1016/j.bcp.2011.03.023. Epub 2011 Apr 6.
6
Pharmacological evidence for a key role of voltage-gated K+ channels in the function of rat aortic smooth muscle cells.电压门控钾通道在大鼠主动脉平滑肌细胞功能中起关键作用的药理学证据。
Br J Pharmacol. 2004 Sep;143(2):303-17. doi: 10.1038/sj.bjp.0705957. Epub 2004 Aug 23.
7
Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels.冈比毒素是由有毒冈比甲藻产生的一种毒素，是电压门控钾通道的强效阻滞剂。
Toxicon. 2008 May;51(6):974-83. doi: 10.1016/j.toxicon.2008.01.004. Epub 2008 Jan 12.
8
Regulation of voltage-gated potassium channels by PI(4,5)P2.PI(4,5)P2 对电压门控钾通道的调节作用。
J Gen Physiol. 2012 Aug;140(2):189-205. doi: 10.1085/jgp.201210806.
9
Animal toxins acting on voltage-gated potassium channels.作用于电压门控钾通道的动物毒素。
Curr Pharm Des. 2008;14(24):2503-18. doi: 10.2174/138161208785777441.
10
Human embryonic stem cell derived cardiac myocytes detect hERG-mediated repolarization effects, but not Nav1.5 induced depolarization delay.人胚胎干细胞衍生的心肌细胞可检测到hERG介导的复极化效应，但检测不到Nav1.5诱导的去极化延迟。
J Pharmacol Toxicol Methods. 2013 Jul-Aug;68(1):74-81. doi: 10.1016/j.vascn.2013.03.001. Epub 2013 Mar 19.
引用本文的文献
1
Implantable bioelectronic devices for photoelectrochemical and electrochemical modulation of cells and tissues.用于细胞和组织的光电化学和电化学调制的可植入生物电子设备。
Nat Rev Bioeng. 2025 Jun;3(6):485-504. doi: 10.1038/s44222-025-00285-7. Epub 2025 Mar 20.
2
Insights into ion channels to identify drug target for neuropathic pain management.深入了解离子通道以确定用于治疗神经性疼痛的药物靶点。
Inflammopharmacology. 2025 Aug 12. doi: 10.1007/s10787-025-01899-4.
3
Spider venom peptides with unique fold selectively block Shaker-type potassium channels.具有独特折叠结构的蜘蛛毒液肽可选择性阻断Shaker型钾通道。
Cell Mol Life Sci. 2025 Aug 8;82(1):300. doi: 10.1007/s00018-025-05778-7.
4
Galangin, a novel Kv7 potassium channel opener, exerts potent antinociceptive effects in multiple chronic pain mouse models.高良姜素是一种新型的Kv7钾通道开放剂，在多种慢性疼痛小鼠模型中发挥强大的镇痛作用。
Acta Pharmacol Sin. 2025 Aug 7. doi: 10.1038/s41401-025-01627-2.
5
Modulation of Redox-Sensitive Cardiac Ion Channels.氧化还原敏感型心脏离子通道的调节
Antioxidants (Basel). 2025 Jul 8;14(7):836. doi: 10.3390/antiox14070836.
6
Membrane-wide screening identifies potential tissue-specific determinants of SARS-CoV-2 tropism.全膜筛选确定了新冠病毒嗜性的潜在组织特异性决定因素。
PLoS Pathog. 2025 Jul 17;21(7):e1013157. doi: 10.1371/journal.ppat.1013157. eCollection 2025 Jul.
7
Voltage gating and 4-aminopyridine inhibition in the Shaker Kv channel revealed by a closed-state model.封闭态模型揭示了Shaker钾通道中的电压门控和4-氨基吡啶抑制作用。
Biophys J. 2025 Jun 24. doi: 10.1016/j.bpj.2025.06.029.
8
Cvill6 and Cvill7: Potent and Selective Peptide Blockers of Kv1.2 Ion Channel Isolated from Mexican Scorpion .Cvill6和Cvill7：从墨西哥蝎子中分离出的Kv1.2离子通道的强效和选择性肽阻断剂
Toxins (Basel). 2025 Jun 4;17(6):279. doi: 10.3390/toxins17060279.
9
Functional control of heteromeric Kv2.1/6.4 channels by the voltage sensor domain of the silent Kv6.4 subunit.沉默型Kv6.4亚基的电压感受器结构域对异源Kv2.1/6.4通道的功能调控
J Physiol. 2025 Jun;603(12):3519-3532. doi: 10.1113/JP288376. Epub 2025 Jun 5.
10
Molecular Diversity and Isoform Evolution in Venom: Insights from Proteomic Analysis.毒液中的分子多样性与异构体进化：蛋白质组学分析的见解
Toxins (Basel). 2025 Apr 23;17(5):210. doi: 10.3390/toxins17050210.
本文引用的文献
1
Recent advances in electrophysiology-based screening technology and the impact upon ion channel discovery research.基于电生理学的筛选技术的最新进展及其对离子通道发现研究的影响。
Methods Mol Biol. 2009;565:187-208. doi: 10.1007/978-1-60327-258-2_9.
2
Kv7 channels as targets for the treatment of pain.作为疼痛治疗靶点的Kv7通道
Curr Pharm Des. 2009;15(15):1773-98. doi: 10.2174/138161209788186326.
3
Electrophysiologic characterization of a novel hERG channel activator.一种新型人乙醚-去极化相关基因（hERG）通道激活剂的电生理特性研究
Biochem Pharmacol. 2009 Apr 15;77(8):1383-90. doi: 10.1016/j.bcp.2009.01.015. Epub 2009 Feb 3.
4
A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.KCNH2的一种灵长类动物特有的脑亚型影响皮层生理学、认知、神经元复极化和精神分裂症风险。
Nat Med. 2009 May;15(5):509-18. doi: 10.1038/nm.1962. Epub 2009 May 3.
5
Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1.缺乏功能性KCNQ1的基因靶向小鼠胰岛素敏感性增强。
Am J Physiol Regul Integr Comp Physiol. 2009 Jun;296(6):R1695-701. doi: 10.1152/ajpregu.90839.2008. Epub 2009 Apr 15.
6
Estrogens and human papilloma virus oncogenes regulate human ether-à-go-go-1 potassium channel expression.雌激素和人乳头瘤病毒癌基因调节人醚-去-去-1钾通道的表达。
Cancer Res. 2009 Apr 15;69(8):3300-7. doi: 10.1158/0008-5472.CAN-08-2036. Epub 2009 Apr 7.
7
hERG1 channel activators: a new anti-arrhythmic principle.人醚 - 去极化激活钾离子通道1（hERG1）通道激活剂：一种新的抗心律失常原理。
Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):347-62. doi: 10.1016/j.pbiomolbio.2009.01.002. Epub 2009 Jan 24.
8
I(Kur)/Kv1.5 channel blockers for the treatment of atrial fibrillation.用于治疗心房颤动的I（Kur）/Kv1.5通道阻滞剂
Expert Opin Investig Drugs. 2009 Apr;18(4):399-416. doi: 10.1517/13543780902762850.
9
Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation.溶血磷脂通过激活TRPV2通道刺激前列腺癌细胞迁移。
Biochim Biophys Acta. 2009 Mar;1793(3):528-39. doi: 10.1016/j.bbamcr.2009.01.003. Epub 2009 Jan 15.
10
A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia.电压门控钾通道编码基因KCNA1中的错义突变与人类常染色体显性低镁血症有关。
J Clin Invest. 2009 Apr;119(4):936-42. doi: 10.1172/JCI36948. Epub 2009 Mar 23.
Zotero 插件