更新于：2024-09-19

KCNA4

更新于：2024-09-19

基本信息

别名

HK1、HPCN2、KCNA4

+ [10]

简介

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772, PubMed:8495559). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:8495559). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA4 forms a potassium channel that opens in response to membrane depolarization, followed by rapid spontaneous channel closure (PubMed:19912772, PubMed:8495559). Likewise, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368).

关联

100 项与 KCNA4 相关的临床结果

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100 项与 KCNA4 相关的转化医学

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0 项与 KCNA4 相关的专利（医药）

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673

项与 KCNA4 相关的文献（医药）

2024-07-01·Journal of Biological Chemistry

Ubiquitination is involved in PKC-mediated degradation of cell surface Kv1.5 channels

Article

作者: Cornwell, James D ; Guo, Jun ; Szendrey, Mark ; Zhang, Shetuan ; Du, Yuan ; Li, Wentao ; Chakraborty, Ananya ; Yang, Tonghua ; Wang, Tingzhong ; Paynter, Amanda

The voltage-gated Kv1.5 potassium channel, conducting the ultra-rapid delayed rectifier K⁺ current (I_Kur) in human cells, plays important roles in the repolarization of atrial action potentials and regulation of the vascular tone. We previously reported that activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) induces endocytic degradation of cell-surface Kv1.5 channels, and a point mutation removing the phosphorylation site, T15A, in the N terminus of Kv1.5 abolished the PMA-effect. In the present study, using mutagenesis, patch clamp recording, Western blot analysis, and immunocytochemical staining, we demonstrate that ubiquitination is involved in the PMA-mediated degradation of mature Kv1.5 channels. Since the expression of the Kv1.4 channel is unaffected by PMA treatment, we swapped the N- and/or C-termini between Kv1.5 and Kv1.4. We found that the N-terminus alone did not but both N- and C-termini of Kv1.5 did confer PMA sensitivity to mature Kv1.4 channels, suggesting the involvement of Kv1.5 C-terminus in the channel ubiquitination. Removal of each of the potential ubiquitination residue Lysine at position 536, 565, and 591 by Arginine substitution (K536R, K565R, and K591R) had little effect, but removal of all three Lysine residues with Arginine substitution (3K-R) partially reduced PMA-mediated Kv1.5 degradation. Furthermore, removing the cysteine residue at position 604 by Serine substitution (C604S) drastically reduced PMA-induced channel degradation. Removal of the three Lysines and Cys604 with a quadruple mutation (3K-R/C604S) or a truncation mutation (Δ536) completely abolished the PKC activation-mediated degradation of Kv1.5 channels. These results provide mechanistic insight into PKC activation-mediated Kv1.5 degradation.

2024-07-01·Neuroscience

Electrophysiological Properties and Morphology of Cardiac and Pulmonary Motoneurons within the Dorsal Motor Nucleus of the Vagus of Rats

Article

作者: Martins Sá, Renato W ; de Souza, Júlia G V ; da Silva, Melina P ; Paton, Julian F R ; de Souza, Daniel P ; da Silva, Carlos A A ; Moraes, Davi J A

The dorsal motor nucleus of the vagus (DMV) contains parasympathetic motoneurons that project to the heart and lungs. These motoneurons control ventricular excitability/contractility and airways secretions/blood flow, respectively. However, their electrophysiological properties, morphology and synaptic input activity remain unknown. One important ionic current described in DMV motoneurons controlling their electrophysiological behaviour is the A-type mediated by voltage-dependent K⁺ (Kv) channels. Thus, we compared the electrophysiological properties, synaptic activity, morphology, A-type current density, and single cell expression of Kv subunits, that contribute to macroscopic A-type currents, between DMV motoneurons projecting to either the heart or lungs of adult male rats. Using retrograde labelling, we visualized distinct DMV motoneurons projecting to the heart or lungs in acutely prepared medullary slices. Subsequently, whole cell recordings, morphological reconstruction and single motoneuron qRT-PCR studies were performed. DMV pulmonary motoneurons were more depolarized, electrically excitable, presented higher membrane resistance, broader action potentials and received greater excitatory synaptic inputs compared to cardiac DMV motoneurons. These differences were in part due to highly branched dendritic complexity and lower magnitude of A-type K⁺ currents. By evaluating expression of channels that mediate A-type currents from single motoneurons, we demonstrated a lower level of Kv4.2 in pulmonary versus cardiac motoneurons, whereas Kv4.3 and Kv1.4 levels were similar. Thus, with the distinct electrical, morphological, and molecular properties of DMV cardiac and pulmonary motoneurons, we surmise that these cells offer a new vista of opportunities for genetic manipulation providing improvement of parasympathetic function in cardiorespiratory diseases such heart failure and asthma.

2024-05-01·Brain and nerve = Shinkei kenkyu no shinpo

[Peripheral Neuropathy and Muscle Disorders as Immune-Related Adverse Events].

Review

作者: Suzuki, Shigeaki

Neurological immune-related adverse events (irAEs) associated with cancer treatment with immune checkpoint inhibitors (ICI) present diverse clinical characteristics. Neurological irAEs affect the peripheral nervous system and muscles more than they affect the central nervous system. Among the various subsets of peripheral neuropathies, polyradiculoneuropathy, which includes Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, stands out as the most severe form, leading to significant muscle weakness. ICIs can induce dysautonomia, including autoimmune autonomic ganglionopathy. Autonomic neuropathy represents a neurological irAE. Neurological irAEs of neuromuscular junctions include myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Diagnosing MG or myositis independently can be challenging when they occur as irAEs. Myocarditis is sometimes observed as an irAE in patients with MG and can cause both severe heart failure and lethal arrhythmias, resulting in fatal outcomes. Anti-Kv1.4 antibodies are biomarkers of the severe form of MG and myocarditis. The administration of ICI in patients with small cell lung cancer increases the risk of LEMS. The distinction between LEMS is an irAE or a manifestation of paraneoplastic neurological syndrome is unclear as both conditions share common immunological mechanisms.

项与 KCNA4 相关的新闻（医药）

2023-09-24

·佰傲谷BioValley

7种神经系统自免疾病

在中枢神经系统（CNS）、周围神经系统（PNS）也存在靶向自身抗原的抗体，通过引起异常免疫反应导致神经性自身免疫性疾病（NAD）发生。主要免疫病理机制与针对神经系统表达的抗原的适应性免疫反应相关，不同病理生理学机制与NAD相关。明确疾病背后的免疫机制是创造更具体治疗方法的重要前提。多发性硬化症（MS）MS是最常见的CNS脱髓鞘疾病，主要在大脑白质束、视神经、髓鞘处存在炎症病变。发生CNS内/外的损伤造成CNS抗原暴露，通过激活异常自身免疫反应使髓鞘受损。APC（巨噬、DC）将抗原吞噬并激活B、T细胞，其中Th1、Th17释放多种促炎白介素引发炎症并向CNS募集其他免疫细胞，CD8+T细胞通过HLA-Ⅰ识别神经元细胞肽，通过细胞毒性作用导致细胞死亡。并且在随后的疾病进展过程中，因髓鞘受损，轴突再生只有星形胶质细胞参与而无髓磷脂。Sciencedirect视神经脊髓炎（NMO）NMO包括横贯性脊髓炎（TM）和急性视神经脊髓炎，主要与水通道蛋白4的自身抗体（AQP4-IgG）相关，各类病毒（CMV、HSV、EBV、ZKV）被确定为NMO的潜在触发因素。感染情况下大脑中CSF、CXCL13、BAFF水平升高，激活B、浆细胞产生AQP4抗体。抗体的存在与视神经炎（ON）患者发生躯干脊髓炎、脑炎有关，并且抗体浓度患者伴有广泛脑损伤、完全失明、急性发作。AQP4-IgG通过Fc段激活补体后还继续激活中性粒（分泌弹性蛋白酶）、嗜酸性粒细胞（产生IL-4），介导炎症发生。格林巴利综合症（GBS）GBS是一种急性炎症性多发性神经根病，主要表现上行性肌无力。全身感染或其他因素诱发的先天免疫反应激活后，引发针对PNS神经根轴突或髓磷脂层的适应性免疫反应，导致急性轴突损伤或髓磷脂快速剥脱。位于轴突细胞膜的神经节苷脂是体液免疫（Ig）的主要目标，导致膜攻击复合物形成和轴突附近巨噬细胞募集来自神经内膜的巨噬细胞是疾病发生中的主角，在被补体激活后：吞噬髓磷脂、轴突成分，产生多种促炎细胞因子（IL-1、IL-12、TNFα）激活浆细胞（产生抗体）和T细胞（产生TNFα和IFNγ）；在TNFα刺激下转化为促炎表型，共同介导疾病的炎症过程。Sciencedirect慢性炎症性脱髓鞘性多发性神经病（CIDP）CIDP是一种炎症性多发性神经病，也以脱髓鞘为特征。主要诱发因素也是感染（细菌、病毒），相关的免疫反应发生在周围神经和脊髓根部。浸润的巨噬、T细胞会导致脱髓鞘和轴突变性，并产生IFNγ、TNFα、IL-2介导炎症发生。巨噬细胞参与脱髓鞘的最后部分；CD4+T细胞会改变BBB，促进粘附分子、IL表达；CD8+T细胞通过细胞毒性作用介导损伤。重症肌无力（MG）MG患者在神经肌肉接头存在AchR和突触后膜相关分子抗体，因信号被阻断导致全身肌肉无力，特别是眼部。这类抗体产生的免疫病理机制尚不完全明确，目前只观察到80%患者有胸腺滤泡增生、10%患者有胸腺瘤。胸腺增生造成GC中B细胞数量增加，而这在正常胸腺中不常见。过量产生的B细胞是抗AchR抗体的来源，也说明针对AchR的耐受性丧失发生胸腺中。并且胸腺中自身反应性T细胞增加也是导致疾病发生的原因，这些T细胞针对肌肉抗原。与MG相关的抗原可分为细胞内抗原和细胞外抗原。抗原‍抗体，作用机制胞外AchR激活补体；阻断Ach结合位点。MuSK屏蔽LRP4和ColQ的结合位点。LRP4激活补体；干扰Agrin和LRP4的结合。Agrin影响MuSK磷酸化，阻止AchR聚集。Colq-Kv1.4-胞内肌动蛋白结合在明暗带之间。兰尼定受体-皮质素-Sciencedirect自身免疫性脑炎（AIE）AIE是由自身免疫引起的脑部疾病，抗体针对细胞内/表面分子。诱因包括感染（主要是HSV）和癌症（主因），且有40%-50%患者病因不明。若是神经系统感染所致，损伤会激活免疫系统识别的抗原，产生异常免疫反应。根据抗体类型也分两类：神经元细胞外抗原抗体，IgG沉积物导致可逆性神经元损伤，中度炎症水平。神经元细胞内抗原抗体，抗体不能被内化，由CTL介导广泛损伤、高水平炎症。胞外抗原N-甲基-D-天冬氨酸受体，AIE的主要原因。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸，多种胸部肿瘤副肿瘤综合征相关。γ-氨基丁酸A/B受体。甘氨酸受体。代谢性谷氨酸受体1/5。腺苷酸激酶5。Ig样细胞粘附分子5（IgLON5）。胞内抗原谷氨酸脱羧酶65，80%T1D患者。大脑中B细胞激活、克隆扩增、成熟，产生的抗体激活补体、NK的细胞杀伤途径，导致细胞死亡。副肿瘤性神经系统疾病（PND）PND发生与肿瘤中存在的神经元蛋白有关。这类蛋白在肿瘤凋亡时释放，被APC摄取并携带至淋巴结递呈给CD4+T细胞然后激活B细胞，B细胞再次接触抗原时分化浆细胞并产生抗体。PND受累部位主要在CNS，肺癌、乳腺癌、淋巴瘤、胃肠道肿瘤依次是PND最常见诱因。PND与AIE相关，针对胞外抗原的抗体会引起AIE，针对胞内抗原则通过CD8+T细胞造成不可逆损伤。Sciencedirect小结这类疾病的治疗采取了多种方法，包括静脉注射Ig、B细胞耗竭、拮抗细胞因子、化疗，但疗效并不统一。未来研究可能在针对遗传、表观遗传学的方向中会为患者带来更具体、更加个性化的治疗方案。参考资料https://www-sciencedirect-com.libproxy1.nus.edu.sg/science/article/pii/B9780323950619000333Acosta-Ampudia Y, Monsalve DM, Ramírez-Santana C. Identifying the culprits in neurological autoimmune diseases [published correction appears in J Transl Autoimmun. 2020 Feb 25;3:100041]. J Transl Autoimmun. 2019;2:100015. Published 2019 Sep 6. doi:10.1016/j.jtauto.2019.100015Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15. doi:10.1111/j.1365-2249.2008.03834.xDarnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003;349(16):1543-1554. doi:10.1056/NEJMra023009本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ ···

免疫疗法临床研究

2023-09-05

·SYNAPSE

礼来收购的Kv1.3阻断剂的前景如何？

Relay Therapeutics最近的日子可能不太好过，美股市场最新股价11块，市值13亿美金左右，较巅峰期市值缩水了4分之3。截至2023年第一季度末, Relay Therapeutics持有9.378亿美元的现金、现金等价物，低于2022年底的10亿美元。该公司预计这些资金将支持到2025年的运营。今年4月份，Relay Therapeutics公布了RLY2608的早期临床数据，股价随即大跌40%，RLY-2608是一种异构体选择性PI3K抑制剂，此类药物在安全性和有效性方面都存在挑战，FDA也曾给予黑框警告。RLY2608的一期试验中仅观察到一个患者的部分反应，且RLY-2608的最佳剂量也未确定，这给药物的安全性和有效性带来了不确定性。虽然到目前为止还没有剂量限制性毒性（DLT）的报告，由于仍处于临床试验的早期阶段，随着研究的继续，可能会出现意想不到的不良反应。 Relay公司还有另外两个有前景的资产。首先是RLY-4008（见图2），小分子抑制剂，可靶向晚期或转移性FGFR2改变的实体瘤患者的FGFR2。其首次人体试验的初步数据显示，对FGFR2具有明显的抑制作用，而不受脱靶毒性的限制（如高磷酸血症）。在2022年与FDA讨论后，Relay选择继续进行FGFR2融合CCA treatment-naïve患者的单臂试验设计，以加快审批速度。RLY-4008已获得FDA和EMA的CCA孤儿药指定。在新药情报库中搜集到2023年5月26号的信息显示，二期推荐剂量为70 mg QD；在分组FGFRi-naïve CCA f/r中，ORR高达55%；在分组Prior-FGFRi CCA f/r中，ORR只有14%；说明接受过FGFRi治疗的患者中，ORR下降比较明显，在不同剂量下，最常见的TRAEs是低级别PPE(57%)、口炎(56%)、口干(38%)、脱发(28%)和眼干(22%)。其次，GDC-1971(以前的RLY-1971)是Relay的另一个主要资产。该药物靶向晚期或转移性实体瘤患者的SHP2。Ia期试验于2022年完成入组。Relay与Genentech就GDC-1971的开发和商业化达成了合作。随着诺华SHP2单药临床因有效性不足而失败，多数公司都在积极开展联用。如上图3，在情报库中搜集到2023年7月公开的一项Ib期研究，旨在评估 GDC-1971与奥西替尼联合治疗不可切除的局部晚期或转移性非小细胞肺癌患者，或与西妥昔单抗联合治疗转移性结直肠癌患者的安全性、药代动力学和活性。该临床招募了172名患者，预计2026年12月底结束试验。主要终点为：不良事件参与者的百分比和有剂量限制性毒性的患者人数。 Relay的上述三款抑制剂都出自D. E. Shaw（DESRES首席科学家），三款药物的差异化方向很明确，都是针对特定蛋白具体亚型做出高选择性靶向。三款药物分别是FGFR2抑制剂RLY-4008、PI3Kα变构抑制剂RLY-2608、SHP2抑制剂RLY-1971。另外，D.E.Shaw还开发了针对自身免疫性疾病和炎症性疾病的小分子抑制剂DES-7114。2022年6月13日，D.E.Shaw Research宣布与礼来公司就Kv1.3抑制剂DES-7114的临床开发和商业化签订了一项全球独家许可协议。礼来将支付6000万美元的首付款，潜在开发和商业里程碑付款高达4.75亿美元，以及全球销售的特许权使用费。 Kv1.3阻断剂的开发难点：对多个亚型需要高度选择性 KV1.3电压门控钾离子通道在质膜和线粒体中参与许多生理过程，主要是在免疫和神经系统中。利用特异性肽和小分子抑制剂靶向KV1.3通道的治疗，在癌症和自身免疫性疾病(如多发性硬化症、I型糖尿病、牛皮癣、接触性皮炎、类风湿性关节炎和重症肌无力)方面显示出巨大的潜力。但是，迄今为止，尚无靶向KV1.3的化合物批准上市。一些具有明确SAR关系的小分子抑制剂已被优化为选择性抑制剂递送到线粒体，这些抑制剂为治疗癌症和自身免疫性疾病提供了治疗潜力。 1999年，小分子WIN17317-3、CP-339818被发现可以靶向Kv1.3通道。然而，这类分子缺乏对通道的选择性和特异性，除 Kv1.3通道外对钠离子通道以及 Kv1.4通道也存在阻断作用，从而导致了潜在的副作用。随后有多种小分子被发现，但都不能很好的解决选择性的问题。除了对钠离子通道和Kv1.4会抑制，对Kv1.1和Kv1.2也会产生阻断。 D.E. Shaw教授表示，DES-7114能够以高选择性的方式抑制离子通道蛋白Kv1.3。临床前研究证明了在几种慢性炎症和自身免疫性疾病(包括溃疡性结肠炎、克罗恩病和特应性皮炎)模型中的有效性，并于2022年初在健康志愿者中成功完成了I期临床试验。但是，时隔一年半，暂时未报道DES-7114临床试验的结果。靶点Kv1.3的研发进展如下表1，据智慧芽新药情报库统计，截止2023年09月04日，全球共有11个Kv1.3药物，来自17个机构，覆盖19个适应症，开展4个临床试验，其中有两个小分子和两个多肽。进展最快的公司是selectION, Inc.，他们在临床1期、临床前和非在研阶段都有1个药物在研发中。对适应症进行分析，如图5所示，目前临床在研适应症均为自身免疫方向，分别是银屑病、银屑病关节炎和特应性皮炎。美国、欧盟和德国是靶点 Kv1.3 药物研发阶段最高的国家/地区。国内公司中，武汉摩尔生物科技有限公司也在该靶点进行了研发，目前处于临床前阶段。 DES-7114的相关专利如下图6，在智慧芽新药情报数据库中搜索D. E. Shaw Research和Kv1.3，共发现82组申请，11个INPADOC同族申请，集中在2022年申请了2个（申请日在3月和5月份）、2020年申请了5个，2021年申请了1个，以及2023年申请了两个；而DES-7114在2022年1月份开始进入一期临床。并且早在2013年9月，D.E. Shaw公司就公开了一种筛选电压门控蛋白的方法。目前临床分子DES-7114的结构尚未公开，只能从2021年和2020年6个INPADOC同族申请去寻找蛛丝马迹。这6篇专利分别是：WO2022076285、WO2021071832、WO2021071812、WO2021071802、WO2021071803、WO2021071821。这几篇专利里面结构的合成难度都不大，不过多数化合物具有几个手性。有一些片段和母核还是比较新的，感兴趣的可以关注一下。但是，这些专利中的化合物多数只公开了对Kv1.3通道抑制的IC50数据和hERG数据，且都只是一个范围，且没有对其他通道（如Kv1.1和Kv1.2）的选择性数据，想要推断具体的结构还是有难度。总结 Relay Therapeutics是近年来一家颇有名气的以计算化学为特色的药物发现公司，而Relay管线中的三款药物都来自D.E. Shaw。虽然Relay公司目前3个临床化合物中，有两个在临床试验中磕磕绊绊，其以分子动力学为特色的药物发现平台对药物开发还是起到了巨大的推动作用。而Kv1.3通道阻断剂的结构类型探索中，20多年来，小分子一直很难做到对Kv1.1和Kv1.2的选择性。D.E. Shaw Research公司在离子通道蛋白亚型的差异化靶向方面具有丰富的经验，除了Kv1.3通道蛋白外，TRPA1阳离子通道蛋白相关专利也有多篇公开。根据智慧芽新药情报库搜集到的情报，目前Kv1.3阻断剂临床主要用于自身免疫疾病的治疗。为了开发更为安全的治疗药物，需重点关注化合物对Kv1X通道亚型(Kv1.1通道和 Kv1.2通道等)的选择性。参考资料： 1.https://seekingalpha.com/article/4620984-relay-therapeutics-stock-market-may-be-prematurely-dismissing-rly-2608. 2.Špela Gubič et.al, Discovery of KV1.3 ion channel inhibitors:Medicinal chemistry approaches and challenges.Med Res Rev. 2021;41:2423–2473. 3.Antonio Felipe et.al; Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target.Biochemical Pharmacology 165 (2019) 214-220. 4.智慧芽新药情报库/专利数据库.

引进/卖出临床结果快速通道孤儿药

2017-03-14

·NS Medical Devices

Researchers develop sweat-based glucose monitoring and maintenance device

Researchers from South Korea’s Center for Nanoparticle Research within the Institute for Basic Science (IBS) have developed a new sweat-based glucose monitoring and maintenance device. Featuring small and sensitive sensors, the sweat-based system enables rapid glucose measurement, helping to provide a multistep and precisely controlled dosage of drug. Earlier, the researchers presented a study on the wearable graphene-based patch that enables diabetes monitoring and feedback therapy by using human sweat. The sweat-based monitoring, which is an alternative approach, is said to provide a painless blood glucose monitoring method for better control of blood glucose levels. To enhance the sweat collection, the researchers redeveloped the system to function under a small amount of sweat. Researchers have used electrochemically active and porous metal electrodes to speed up the sensitivity of the system. The miniaturized sensor design of the device enables sweat analysis even with 1µl of sweat. The first author of the study Dr. LEE Hyunjae said: "It was quite a challenge to find the optimal size of the sensors. If the size is too small, the signal becomes too small or the surface functionalization becomes difficult to handle.” For precise reading and feedback therapy, the patch system integrates an additional sweat uptake layer that includes soluble and porous carbohydrate network, as well as waterproof band to facilitate the sweat collection. In addition, the system allows precise and timely drug delivery. Drugs for the feedback therapy will be loaded on two different temperature-responsive phase change nanoparticles (PCNs), which are implanted in the microneedles that additionally coated with phase change materials (PCMs). The integrated heater modulates thermal actuation to activate either PCN1 alone or both PCNs, once the system detects a high glucose level. Controlled by three multichannel heaters, the thermos-responsive microneedles can deliver the drug up to six steps of drug dosages in response to the measured sweat glucose level. The researchers reported that the blood glucose level has been suppressed significantly when the more drug is delivered to the diabetic mice. Image: Researchers from the Institute for Basic Science have designed sweat-based glucose monitoring and maintenance device. Photo: courtesy of Institute for Basic Science.