更新于：2024-11-01

KCNJ8 x ABCC9

更新于：2024-11-01

基本信息

关联

项与 KCNJ8 x ABCC9 相关的药物

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

100 项与 KCNJ8 x ABCC9 相关的临床结果

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100 项与 KCNJ8 x ABCC9 相关的转化医学

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0 项与 KCNJ8 x ABCC9 相关的专利（医药）

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项与 KCNJ8 x ABCC9 相关的文献（医药）

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.

2023-09-01·Physiological Genomics

Altered placental ion channel gene expression in preeclamptic high-altitude pregnancies

Article

作者: Fallahi, Sahand ; Shortt, Jonathan A. ; Houck, Julie A. ; Krause, Bernardo J. ; Julian, Colleen G. ; Lazo-Vega, Litzi ; Moore, Lorna G. ; Toledo-Jaldin, Lilian ; Miranda-Garrido, Valquiria ; Diamond, Breea ; Matarazzo, Christopher J. ; Lorca, Ramón A.

High-altitude (>2,500 m) residence increases the risk of pregnancy vascular disorders such as fetal growth restriction and preeclampsia, each characterized by impaired placental function. Genetic attributes of highland ancestry confer relative protection against vascular disorders of pregnancy at high altitudes. Although ion channels have been implicated in placental function regulation, neither their expression in high-altitude placentas nor their relationship to high-altitude preeclampsia has been determined. Here, we measured the expression of 26 ion-channel genes in placentas from preeclampsia cases and normotensive controls in La Paz, Bolivia (3,850 m). In addition, we correlated gene transcription to maternal and infant ancestry proportions. Gene expression was assessed by PCR, genetic ancestry evaluated by ADMIXTURE, and ion channel proteins localized by immunofluorescence. In preeclamptic placentas, 11 genes were downregulated ( ABCC9, ATP2A2, CACNA1C, KCNE1, KCNJ8, KCNK3, KCNMA1, KCNQ1, KCNQ4, PKD2, and TRPV6) and two were upregulated ( KCNQ3 and SCNN1G). KCNE1 expression was positively correlated with high-altitude Amerindian ancestry and negatively correlated with non-high altitude. SCNN1G was negatively correlated with African ancestry, despite minimal African admixture. Most ion channels were localized in syncytiotrophoblasts (Cav1.2, TRPP2, TRPV6, and Kv7.1), whereas expression of Kv7.4 was primarily in microvillous membranes, Kir6.1 in chorionic plate and fetal vessels, and MinK in stromal cells. Our findings suggest a role for differential placental ion channel expression in the development of preeclampsia. Functional studies are needed to determine processes affected by these ion channels in the placenta and whether therapies directed at modulating their activity could influence the onset or severity of preeclampsia.

2023-09-01·The Journal of pharmacology and experimental therapeutics

Rapid Characterization of the Functional and Pharmacological Consequences of Cantú Syndrome K_ATP Channel Mutations in Intact Cells.

Article

作者: McClenaghan, Conor ; Matreyek, Kenneth A ; Gao, Jian ; Nichols, Colin G ; Grange, Dorothy K

Gain-of-function of K_ATP channels, resulting from mutations in either KCNJ8 (encoding inward rectifier sub-family 6 [Kir6.1]) or ABCC9 (encoding sulphonylurea receptor [SUR2]), cause Cantú syndrome (CS), a channelopathy characterized by excess hair growth, coarse facial appearance, cardiomegaly, and lymphedema. Here, we established a pipeline for rapid analysis of CS mutation consequences in Landing pad HEK 293 cell lines stably expressing wild type (WT) and mutant human Kir6.1 and SUR2B. Thallium-influx and cell membrane potential, reported by fluorescent Tl-sensitive Fluozin-2 and voltage-sensitive bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) dyes, respectively, were used to assess channel activity. In the Tl-influx assay, CS-associated Kir6.1 mutations increased sensitivity to the ATP-sensitive potassium (K_ATP) channel activator, pinacidil, but there was strikingly little effect of pinacidil for any SUR2B mutations, reflecting unexpected differences in the molecular mechanisms of Kir6.1 versus SUR2B mutations. Compared with the Tl-influx assay, the DiBAC4(3) assay presents more significant signal changes in response to subtle K_ATP channel activity changes, and all CS mutants (both Kir6.1 and SUR2B), but not WT channels, caused marked hyperpolarization, demonstrating that all mutants were activated under ambient conditions in intact cells. Most SUR2 CS mutations were markedly inhibited by <100 nM glibenclamide, but sensitivity to inhibition by glibenclamide, repaglinide, and PNU37883A was markedly reduced for Kir6.1 CS mutations. Understanding functional consequences of mutations can help with disease diagnosis and treatment. The analysis pipeline we have developed has the potential to rapidly identify mutational consequences, aiding future CS diagnosis, drug discovery, and individualization of treatment. SIGNIFICANCE STATEMENT: We have developed new fluorescence-based assays of channel activities and drug sensitivities of Cantú syndrome (CS) mutations in human Kir6.1/SUR2B-dependent K_ATP channels, showing that Kir6.1 mutations increase sensitivity to potassium channel openers, while SUR2B mutations markedly reduce K channel opener (KCO) sensitivity. However, both Kir6.1 and SUR2B CS mutations are both more hyperpolarized than WT cells under basal conditions, confirming pathophysiologically relevant gain-of-function, validating DiBAC4(3) fluorescence to characterize hyperpolarization induced by K_ATP channel activity under basal, non KCO-activated conditions.