KCa1.1 channels as therapeutic targets for rheumatoid arthritis.
KCa1.1 channels as therapeutic targets for rheumatoid arthritis.
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DOI：
10.1080/14728222.2017.1398234
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发表时间：
2017-12
影响因子：
5.8
通讯作者：
Beeton C
中科院分区：
文献类型：
--
作者：
Beeton C
类风湿性关节炎（RA）是一种慢性全身性自身免疫性疾病。它优先靶向关节，但在其他器官（如呼吸系统和心血管系统）中显示合并症。尽管在过去的几十年中，RA的治疗选择有了相当大的改善，但在使用疾病调节性抗风湿药物（单独或与甲氨蝶呤联合）治疗2年后，只有60-70%的患者症状减轻20%，只有45-50%的患者放射性损伤进展减缓[1]。除了对某些患者的有限益处外，现有治疗还会引起显著的副作用，包括感染和淋巴瘤的风险和严重程度增加[2]。需要新的治疗药物来治疗RA，除了免疫细胞外，常驻关节细胞如成纤维细胞样滑膜细胞（FLS）在RA发病机制中发挥作用[3]。FLS在健康条件下形成关节的衬里。在RA期间，FLS获得通常被描述为L肿瘤样L的侵袭性表型，其特征在于侵袭性、接触抑制的丧失以及蛋白酶、血管生成因子和细胞因子的分泌。因此，这些细胞已被提议作为治疗RA的非免疫细胞靶点。然而，目前没有一种RA治疗剂特异性靶向FLS。离子通道是继G蛋白偶联受体之后的第二大信号转导蛋白家族[4]。每个细胞表达各种离子通道，可渗透选定的离子，但它们的身份不同的细胞类型。表达的通道的这种多样性允许基于表达的离子通道的组合选择性靶向细胞。超过70个基因单独编码钾通道成孔α亚基，创造了显着的多样性，通过一些钾通道的调节亚基和亚基的剪接变体的存在而增强。钾通道是细胞膜电位、增殖和迁移、细胞因子、神经递质和激素分泌以及动作电位波形的重要调节剂。因此，人们正在广泛研究这一系列通道，以寻找各种疾病的靶点[5]。钙和电压门控钾通道KCa 1。1（aka BK，MaxiK，Slo 1，KCNMA 1）作为治疗靶点特别令人感兴趣，因为其调节亚基和其剪接变体的组织限制性分布。
Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease. It preferentially targets diarthrodial joints but displays comorbidities in other organs, such as the respiratory and cardiovascular systems. Although therapeutic options for RA have considerably improved in the last decades, only 60-70% of patients achieve a 20% reduction in symptoms and only 45-50% of patients have a reduction in progression of radiological damage after 2 years of treatment with diseasemodifying antirheumatic drugs, alone or in combination with methotrexate [1]. In addition to limited benefits for some patients, existing treatments cause significant side effects, including an increased risk and severity of infections and lymphoma [2]. New therapeutic agents that spare the immune system are needed to treat RA.Besides immune cells, resident joint cells such as fibroblastlike synoviocytes (FLS) play a role in RA pathogenesis [3]. FLS form the lining of the joint under healthy conditions. During RA, FLS acquire an aggressive phenotype often described as Ltumor likeL and characterized by invasiveness, loss of contact inhibition, and secretion of proteases, angiogenic factors, and cytokines. These cells have therefore been proposed as nonimmune cell targets for the treatment of RA. However, none of the current RA therapeutics specifically target FLS. Ion channels represent the second largest family of signal transduction proteins after G protein-coupled receptors [4]. Each cell expresses various ion channels permeable to selected ions but their identity differs between cell types. This diversity in channels expressed allows for selective targeting of cells based on the combination of ion channels expressed. More than 70 genes encode for potassium channel pore-forming α subunits alone, creating remarkable diversity that is enhanced by the existence of regulatory subunits for some potassium channels, and splice variants of subunits. Potassium channels are crucial regulators of cell membrane potential, proliferation and migration, of secretion of cytokines, neurotransmitters and hormones, and of action potential waveforms. This family of channels is therefore extensively being studied to search for targets for a broad array of diseases [5]. The calcium-and voltage-gated potassium channel KCa1. 1 (aka BK, MaxiK, Slo1, KCNMA1) is of particular interest as a therapeutic target because of the tissue-restricted distribution of its regulatory subunits and of the splice variants of
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