更新于：2024-11-01

ABCC9

更新于：2024-11-01

基本信息

别名

ABCC9、ATP binding cassette subfamily C member 9、ATP-binding cassette sub-family C member 9

+ [4]

简介

Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation.

关联

项与 ABCC9 相关的药物

Minoxidil

米诺地尔

靶点

ABCC9 x Kir6.2

作用机制

ABCC9 agonists [+1]

在研机构

JOHNSON AND JOHNSON GROUP CONSUMER COMPANIES [+4]

原研机构

Pfizer Inc.

在研适应症

高血压 [+4]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1979-10-18

VU-0542270

靶点

ABCC9 x KCNJ8

作用机制

ABCC9 抑制剂 [+1]

在研机构

Vanderbilt University

原研机构

Vanderbilt University

在研适应症

心血管疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

148

项与 ABCC9 相关的临床试验

ChiCTR2400088536 / SuspendedIIT

Clinical study of new polymer polylactic acid microneedle combined with 5% minoxidil application for the treatment of male androgenetic alopecia

开始日期2024-10-31

申办/合作机构

中日友好医院

CTRI/2024/10/074861 / Not yet recruitingN/A

Compare the safety and efficacy of Tugain Eva (minoxidil 5 percent solution fortified with 0.0033 percent melatonin) with Tugain solution (minoxidil 5 percent solution) in female pattern hair loss - NIL

开始日期2024-10-15

申办/合作机构

Cipla Ltd.

CTRI/2024/09/073394 / Not yet recruiting临床1期IIT

Efficacy of autologous Growth Factor Concentrate injection and Platelet Rich Plasma injection in patients of Androgenic Alopecia receiving topical minoxidil: A randomized control trial - NIL

开始日期2024-09-22

申办/合作机构-

100 项与 ABCC9 相关的临床结果

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100 项与 ABCC9 相关的转化医学

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0 项与 ABCC9 相关的专利（医药）

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221

项与 ABCC9 相关的文献（医药）

2024-10-10·Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics

[Clinical characteristics and genetic analysis of a child with Cantú syndrome due to variant of ABCC9 gene].

Article

作者: Li, Yingying ; Wang, Fangjie ; Yao, Xiaoli ; Hou, Weina ; He, Kun ; Xiao, Mengjun

OBJECTIVETo explore the clinical characteristics and pathogenic variant in a child with Cantú syndrome (CS).METHODSA male who was admitted to the Children's Hospital Affiliated to Zhengzhou University on February 23, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to whole-exome sequencing (WES). Candidate variant was verified by Sanger sequencing. This study was approved by the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2023-K-087).RESULTSThe child, a 3-year-and-2-month-old male, was born with hirsutism, with heavy hair all over the body and peculiar facial features. Routine echocardiography 1 month before had discovered atrial septal defect. Sequencing revealed that the child has harbored a heterozygous c.2438G>C (p.S813T) variant of the ABCC9 gene, which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2438G>C variant was classified as likely pathogenic (PS2+PM2_Supporting+PP3).CONCLUSIONThe heterozygous c.2438G>C variant of the ABCC9 gene probably underlay the pathogenesis of CS in this child.

2024-09-10·JCI Insight

Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome

Article

作者: Yamasaki, Evan ; Radi, Rafael ; Lavanderos, Boris ; Nichols, Colin G ; Metwally, Elsayed ; Earley, Scott ; McClenaghan, Conor ; Feng Earley, Yumei ; Rios, Natalia ; Thakore, Pratish ; Sanchez Solano, Alfredo

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.

2024-09-01·Ultrasound in Obstetrics & Gynecology

EP18.19: Prenatal diagnosis of Cantú syndrome during the second trimester due to a novel ABCC9 pathogenic variant: a case report

Article

作者: D'Ambrosio, V. ; Grammatico, P. ; Bottillo, I. ; Rizzo, G. ; Giancotti, A. ; Vasta, A. ; Di Mascio, D. ; Formicola, D. ; Bacigalupo, F. ; Pizzuti, A.

项与 ABCC9 相关的新闻（医药）

2023-06-26

·生物谷

Nat. Commun. | 陈雷课题组发现SUR2A上的R螺旋抑制了KATP通道的激活

2023年6月17日，北京大学未来技术学院分子医学研究所、北大-清华生命科学联合中心陈雷课题组在Nature Communications杂志上发表了题为“The inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix”的论文。该研究通过解析SUR2A和SUR2B在抑制剂瑞格列奈（RPG）和不同Mg-核苷酸存在的条件下的一系列冷冻电镜结构，发现了SUR2A上存在的一段此前从未被报道过的可以抑制KATP通道的螺旋，链接见：https://www.nature.com/articles/s41467-023-39379-4。KATP (ATP敏感的钾离子通道) 的活性被细胞内ATP抑制，被Mg-ADP激活。它们可以将细胞的能量代谢水平与细胞电信号偶联[1]。KATP通道是由四个Kir6亚基及四个SUR亚基组成的异源八聚体。其中Kir6亚基形成了钾离子外流的中心孔道区[2]，SUR亚基作为调节型亚基通过结合激活剂（Mg-ADP，KATP开放剂）和抑制剂（胰岛素促泌剂）来调控通道开关[3]。SUR亚基共有三种亚型，SUR1，SUR2A和SUR2B，其中SUR2A和SUR2B是由ABCC9基因编码的不同剪接体，仅C末端42个氨基酸存在差异[1]。SUR2A在心肌和骨骼肌中发挥重要作用，SUR2B主要分布于平滑肌[2, 4]。ABCC9基因发生突变导致扩张型心肌病[5]、家族性房颤[6]、Cantu综合征[7]等疾病的发生。SUR蛋白属于ABC超家族，含有两个跨膜区（Transmembrane domain ，TMD）和两个胞内核苷酸结合结构域（Nucleotide-binding domain ，NBD）[3]，NBD二聚化促进TMD1和TMD2的靠近[8]。尽管不同的SUR亚基具有较高的序列相似性，Mg-ADP和KATP开放剂对不同亚型激活效果不同：相比于SUR1和SUR2B，SUR2A对Mg-ADP的激活响应明显较弱[9-17]。SUR2A的这种特性保证了心肌细胞在正常工作时不会导致KATP通道的激活，以避免其对心脏正常电信号的影响。陈雷课题组此前已经解析了SUR2A和SUR2B在NBD1结合Mg-ATP，NBD2结合Mg-ADP的occluded（OD）状态下的结构（SUR2OD/ATP/ADP）[18]。但这些结构并无法解释SUR2A对Mg-ADP激活作用的响应为何比其它SUR弱。在此项研究中，陈雷课题组使用RPG抑制了SUR从Inward-facing (IF)构象向OD构象的完全转变，解析了一系列SUR2A和SUR2B在有Mg-核苷酸存在情况下的结构。研究者在NBD1和NBD2结合Mg-ATP的SUR2A（SUR2AIF/MgATP/MgATP）结构中观察到一段清晰的螺旋密度（924-942），这段螺旋与NBD1相连，结合于NBD1和NBD2之间，因此将其命名为调节螺旋（R螺旋）。R螺旋一侧通过R930和L933与NBD1上D789以及L792，L793和I806组成的疏水口袋相互作用，另一侧通过Y938，K931和R935与NBD2上结合的ATP相互作用。但研究者在NBD2结合Mg-ADP状态下的结构里（SUR2AIF/MgATP/MgADP），发现NBD产生了一定程度的相互靠近，而且未观察到R螺旋，表明Mg-ADP破坏了R螺旋与NBD的相互作用（图1）。图1 不同核苷酸结合状态下SUR2A中R螺旋的电子密度研究者在Mg-ATP结合状态下的SUR2B结构中同样观察到了R螺旋的密度，但其密度较差，说明其动态性较高。在NBD2结合Mg-ADP时，SUR2B主要呈现出两种构象，其中SUR2BIF/MgATP/MgADP类似于SUR2AIF/MgATP/MgADP，R螺旋密度模糊且不连续；另一种状态下SUR2BIF/MgATP/MgADP 的NBD更加相互靠近，R螺旋密度完全消失（图2）。图2 不同核苷酸结合状态下SUR2B的构象及R螺旋的电子密度研究者通过突变体的电生理功能实验发现：将SUR2A的R螺旋上与NBD1 和NBD2 相互作用的氨基酸突变会导致Mg-ADP对KATP通道的激活增强，说明R螺旋对KATP通道起抑制作用，这和其独特的空间位置相一致。综上，该研究阐明了R螺旋通过抑制SUR2A的NBD二聚化来抑制KATP通道的结构机制（图3），提出了SUR2B-C42可能通过别构作用促进Mg-ADP与NBD2的结合，进一步导致R螺旋的解离和NBD二聚化以及KATP通道的激活。这项工作为进一步深入研究不同亚型KATP通道的调控机制打下了基础。图3 R螺旋参与调节SUR2A蛋白构象变化的结构模型原文链接：https://www.nature.com/articles/s41467-023-39379-4

寡核苷酸抗体药物偶联物临床2期临床1期临床终止