Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain; Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Molecular Physiology Laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
Biochem Pharmacol. 2024 Aug;226:116368. doi: 10.1016/j.bcp.2024.116368. Epub 2024 Jun 14.
The voltage-dependent potassium channel Kv1.3 is a promising therapeutic target for the treatment of autoimmune and chronic inflammatory disorders. Kv1.3 blockers are effective in treating multiple sclerosis (fampridine) and psoriasis (dalazatide). However, most Kv1.3 pharmacological antagonists are not specific enough, triggering potential side effects and limiting their therapeutic use. Functional Kv are oligomeric complexes in which the presence of ancillary subunits shapes their function and pharmacology. In leukocytes, Kv1.3 associates with KCNE4, which reduces the surface abundance and enhances the inactivation of the channel. This mechanism exerts profound consequences on Kv1.3-related physiological responses. Because KCNE peptides alter the pharmacology of Kv channels, we studied the effects of KCNE4 on Kv1.3 pharmacology to gain insights into pharmacological approaches. To that end, we used margatoxin, which binds the channel pore from the extracellular space, and Psora-4, which blocks the channel from the intracellular side. While KCNE4 apparently did not alter the affinity of either margatoxin or Psora-4, it slowed the inhibition kinetics of the latter in a stoichiometry-dependent manner. The results suggested changes in the Kv1.3 architecture in the presence of KCNE4. The data indicated that while the outer part of the channel mouth remains unaffected, KCNE4 disturbs the intracellular architecture of the complex. Various leukocyte types expressing different Kv1.3/KCNE4 configurations participate in the immune response. Our data provide evidence that the presence of these variable architectures, which affect both the structure of the complex and their pharmacology, should be considered when developing putative therapeutic approaches.
电压门控钾通道 Kv1.3 是治疗自身免疫和慢性炎症性疾病的有前途的治疗靶点。Kv1.3 阻断剂在治疗多发性硬化症（fampridine）和银屑病（dalazatide）方面非常有效。然而，大多数 Kv1.3 药理学拮抗剂不够特异，引发潜在的副作用并限制了它们的治疗用途。功能性 Kv 是多聚体复合物，其中辅助亚基的存在塑造了它们的功能和药理学。在白细胞中，Kv1.3 与 KCNE4 相关联，后者减少通道的表面丰度并增强其失活。这种机制对与 Kv1.3 相关的生理反应产生了深远的影响。由于 KCNE 肽改变 Kv 通道的药理学，我们研究了 KCNE4 对 Kv1.3 药理学的影响，以深入了解药理学方法。为此，我们使用了 margatoxin，它从细胞外空间结合通道孔，以及 Psora-4，它从细胞内侧面阻断通道。虽然 KCNE4 显然没有改变 margatoxin 或 Psora-4 的亲和力，但它以依赖于计量的方式减缓了后者的抑制动力学。结果表明在存在 KCNE4 的情况下 Kv1.3 结构发生了变化。数据表明，虽然通道口的外部部分保持不变，但 KCNE4 会干扰复合物的细胞内结构。表达不同 Kv1.3/KCNE4 构型的各种白细胞类型参与免疫反应。我们的数据提供了证据，表明这些可变结构的存在，既影响复合物的结构又影响其药理学，在开发潜在的治疗方法时应予以考虑。
