Special collection on inward rectifying K+ channels.
Special collection on inward rectifying K+ channels.
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内向整流K通道特别合集。
DOI：
10.1152/ajpcell.00457.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Delpire,Eric
中科院分区：
文献类型：
--
作者：
Denton,JerodS;Delpire,Eric
内向整流钾电流(KIR)最早是由Bernard Katz爵士于1949年从青蛙骨骼肌中记录到的。与当时已知的神经细胞膜的去极化激活、向外整流的延迟整流钾电流不同，Katz观察到这些异常电流表现出不寻常的电压依赖性，并优先向内携带钾电流。在过去的70年里，这个领域经历了巨大的增长，因为我们现在知道这些异常的内向整流电流是由KIR通道携带的，KIR通道家族由16个基因(称为KCNJx)组成，并且这些基因在可兴奋和不可兴奋的细胞中以特定细胞类型的方式表达。编码的蛋白质在不同的细胞、组织和器官过程中扮演着重要的角色，从调节激素分泌到维持心脏、血管系统、神经系统和肾脏的复杂生理。致病突变的发现和转基因啮齿动物模型的研究消除了人们对它们对人类健康重要性的任何怀疑。一些KIR通道是假定的药物靶点，随着不断努力开发通道家族(2-5)的药理学，评估它们的治疗潜力成为可能。为了庆祝和总结这一令人兴奋的领域的现状，我们召集了KIR通道生物学的领先专家，在《美国生理学-细胞生理学》(https://journals.)杂志上进行了特别收藏生理学。Org/topic/ajpcell-collections/inward-rectifying-kþ频道)。在他们的综述文章中，Conor McClenaghan博士和Colin Nichols博士(6)讨论了心血管特异的、ATP调节的KIR(KATP)通道在一种新描述的称为坎图综合征(CS)的遗传病中的作用。在CS下面的KATP通道由Kir6组成。1(由KCNJ8编码；表1)成孔亚基和调节性磺脲受体2B(SUR2B)亚单位(由ABCC9编码；表1)，主要在动脉平滑肌(ASM)细胞中表达。任何一个亚基的功能获得(GOF)突变都会导致CS，CS的特征是各种病理变化，包括毛发过度生长、面部变形、心脏增大、血管阻力降低和其他疾病。新的临床证据表明，使用非特异性KATP通道抑制剂格列本脲治疗患者可以逆转疾病的某些方面。作者讨论了这种治疗策略的挑战和开发针对Kir6的特异性抑制药物的迫切需要。1/SUR2B。Michael Davis博士、Kim博士和Nichols博士(7)讨论了KATP通道在淋巴管功能中的作用以及它们治疗淋巴水肿的未开发的治疗潜力。作者批判性地评估了淋巴平滑肌(LSM)细胞主要表达Kir6的证据。1/SUR2B KATP通道，并讨论它们在调节基础淋巴管功能和对血管扩张激动剂的反应中的作用。超过一半的CS患者出现淋巴水肿，可能是由于LSM KATP通道过度活跃所致。为了支持这一观点，在KCNJ8(Kir6.1)表现为严重的淋巴管功能障碍。已经建立了几个携带特定CS突变的转基因小鼠模型，并等待研究。作者最后仔细回顾了表明淋巴KATP通道可能导致由淋巴收缩受损引起的原发性淋巴水肿，以及充血性心力衰竭、肥胖和代谢综合征引起的继发性淋巴水肿的证据。…的William Coetzee博士
Inward rectifier potassium (Kir) currents were first recorded from frog skeletal muscle by Sir Bernard Katz in 1949 (1). Unlike the depolarization-activated, outwardly rectifying, delayed rectifier potassium (K þ) currents of nerve cell membranes that were known at the time, Katz observed that these “anomalous” currents exhibited an unusual voltage dependency and preferentially carried K þ current inwardly. The field has experienced tremendous growth during the last 70 years, as we now know that those anomalous inward rectifier currents are carried by Kir channels, and that the Kir channel family is made up of 16 genes (termed KCNJx), and that the genes are expressed in a cell-type-specific manner in both excitable and nonexcitable cells. The encoded proteins play fundamentally important roles in diverse cellular, tissue, and organ processes, ranging from regulation of hormone secretion to maintaining the complex physiology of the heart, vascular system, nervous system, and kidneys. The discovery of disease-causing mutations and studies of transgenic rodent models has removed any doubt of their importance for human health. Some Kir channels are putative drug targets, and, with ongoing efforts to develop the pharmacology of the channel family (2–5), evaluating their therapeutic potential is becoming possible. To celebrate and summarize the current state of this exciting field, we have assembled leading experts in Kir channel biology for a Special Collection in the American Journal of Physiology-Cell Physiology (https://journals. physiology. org/topic/ajpcell-collections/inward-rectifying-kþ channels). In their review article, Drs. Conor McClenaghan and Colin Nichols (6) discuss the role of cardiovascular-specific, ATP-regulated Kir (KATP) channels in a newly described genetic disease called Cantu syndrome (CS). The KATP channels underlying CS are made up of the Kir6. 1 (encoded by KCNJ8; Table 1) pore-forming subunits and regulatory sulfonylurea receptor 2B (SUR2B) subunits (encoded by ABCC9; Table 1) and are expressed primarily in arterial smooth muscle (ASM) cells. Gain-of-function (GOF) mutations in either subunit cause CS, which is characterized by diverse pathologies including excessive hair growth, facial dysmorphia, enlarged heart, reduced vascular resistance, and other disorders. New clinical evidence suggests that the treatment of patients with the nonspecific KATP channel inhibitor, glibenclamide, can reverse certain aspects of the disease. The authors discuss the challenges of this treatment strategy and critical need for developing inhibitory drugs that are specific for Kir6. 1/SUR2B. Drs. Michael Davis, Kim, and Nichols (7) discuss the role of KATP channels in lymphatic vessel function and their untapped therapeutic potential for treating lymphedema. The authors critically evaluate evidence that lymphatic smooth muscle (LSM) cells primarily express Kir6. 1/SUR2B KATP channels and discuss their role in regulating basal lymphatic vessel function and responses to vasodilatory agonists. More than half of patients with CS develop lymphedema, presumably due to overactive LSM KATP channels. In support of this idea, mice carrying a GOF mutation in KCNJ8 (Kir6. 1) exhibit severe lymphatics dysfunction. Several transgenic mouse models carrying specific CS mutations have been generated and await investigation. The authors conclude with a careful review of evidence suggesting that lymphatic KATP channels might contribute to primary lymphedema caused by impaired lymphatic contraction, as well as secondary lymphedema in the setting of congestive heart failure, obesity, and metabolic syndrome. Drs. William Coetzee …