Last update 01 Nov 2024

KCNJ8

Last update 01 Nov 2024

Basic Info

Synonyms

ATP-sensitive inward rectifier potassium channel 8, Inward rectifier K(+) channel Kir6.1, KCNJ8

+ [5]

Introduction

This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium (By similarity).

Drugs associated with KCNJ8

VU-0542270

Target

ABCC9 x KCNJ8

Mechanism

ABCC9 inhibitors [+1]

Active Org.

Vanderbilt University

Originator Org.

Vanderbilt University

Active Indication

Cardiovascular Diseases

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KCNJ8

100 Translational Medicine associated with KCNJ8

0 Patents (Medical) associated with KCNJ8

590

Literatures (Medical) associated with KCNJ8

01 Dec 2024·Channels (Austin, Tex.)

Characterization of four structurally diverse inhibitors of SUR2-containing K_ATP channels.

Article

Author: Denton, Jerod ; Li, Kangjun ; Satpute Janve, Vaishali

Vascular smooth muscle ATP-sensitive potassium (K_ATP) channels play critical roles in modulating vascular tone and thus represent important drug targets for diverse cardiovascular pathologies. Despite extensive research efforts spanning several decades, the search for selective inhibitors that can discriminate between vascular K_ATP (i.e. Kir6.1/SUR2B) and pancreatic and brain K_ATP (i.e. Kir6.2/SUR1) channels has, until recently, been unsuccessful. Our group therefore carried out a high-throughput screen of chemically diverse compounds with the goal of discovering specific Kir6.1/SUR2B inhibitors. This screen identified several novel classes of Kir6.1/SUR2B inhibitors, including the first potent (IC₅₀ ~100 nM) and selective inhibitor published to date, termed VU0542270. Here, we expand on this work by disclosing the identity and pharmacological properties of four additional Kir6.1/SUR2B inhibitors that are structurally unrelated to Kir to VU0542270. These inhibitors, named VU0212387, VU0543336, VU0605768, and VU0544086, inhibit Kir6.1/SUR2B with IC₅₀ values ranging from approximately 100 nM to 1 µM and exhibit no apparent inhibitory activity toward Kir6.2/SUR1. Functional analysis of heterologously expressed subunit combinations of Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B and demonstrated that all four inhibitors act on SUR2 to induce channel inhibition. Interestingly, VU0543336 and VU0212387 exhibit paradoxical stimulatory effects on Kir6.2/SUR1 at higher doses. This study broadens our understanding of K_ATP channel pharmacology, generally, and reveals novel chemical matter for the development of Kir6.1/SUR2-selective drugs, specifically.

10 Sep 2024·Function (Oxford, England)

Electrophysiology of Human iPSC-derived Vascular Smooth Muscle Cells and Cell-autonomous Consequences of Cantú Syndrome Mutations.

Article

Author: McClenaghan, Conor ; Weng, Kuo-Chan ; Grange, Dorothy K ; Nichols, Colin G ; Colijn, Sarah ; Halabi, Carmen M ; Stratman, Amber N ; Silva, Jonathan R ; Hanson, Alex

Cantú syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by gain-of-function (GoF) variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels and is characterized by low systemic vascular resistance, as well as tortuous, dilated, vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs .

10 Sep 2024·JCI Insight

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

Article

Author: 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.

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KCNJ8

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