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Last update 08 May 2025

KCNJ8

Last update 08 May 2025

Basic Info

Synonyms

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

+ [5]

Introduction

Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it (PubMed:20558321, PubMed:21836131, PubMed:24700710, PubMed:28842488). 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 (PubMed:20558321, PubMed:21836131, PubMed:24700710, PubMed:28842488). The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium (PubMed:20558321, PubMed:21836131, PubMed:24700710, PubMed:28842488). Can form a sulfonylurea-sensitive but ATP-insensitive potassium channel with ABCC9 (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

584

Literatures (Medical) associated with KCNJ8

01 Jan 2025·JACC: Clinical Electrophysiology

Transcriptomic Profiling of Human Myocardium at Sudden Death to Define Vulnerable Substrate for Lethal Arrhythmias

Article

Author: Connolly, Andrew J ; Schwarzer-Sperber, H S ; Nakasuka, Kosuke ; Feng, Jean ; Schwarzer, Roland ; Wu, Joseph C ; Caudal, Arianne ; Maison, David P ; Liu, Yu ; Henrich, Timothy J ; Padmanabhan, Arun ; Pang, Paul D ; Tseng, Zian H ; Moffatt, Ellen

BACKGROUNDWhile some chronic pathological substrates for sudden cardiac death (SCD) are well known (eg, coronary artery disease and left ventricular [LV] dysfunction), the acute vulnerable myocardial state predisposing to fatal arrhythmia remains a critical barrier to near-term SCD prevention.OBJECTIVESThis study sought to define the distinct myocardial transcriptomic profile of autopsy-defined arrhythmic sudden deaths, compared to nonarrhythmic sudden deaths and trauma deaths, to determine the acute vulnerable state in the hours to days before SCD.METHODSWe used autopsy to adjudicate arrhythmic from nonarrhythmic causes in 1,265 sudden deaths in San Francisco County from 2011 to 2018. We performed a degradation-tolerant transcriptomic evaluation of LVs sampled at the time of SCD from 245 consented cases using a curated panel of 448 gene probes with known or hypothesized association with SCD.RESULTSThe targeted transcriptome of arrhythmic (n = 129) vs nonarrhythmic (n = 90 nonarrhythmic sudden deaths + 26 trauma deaths) LV samples revealed 31 differentially up-regulated and 36 down-regulated genes (adjusted P < 0.05) related to the collagen-containing extracellular matrix (up-regulation of FAP, FMOD, and LTBP2), regulation of ion transport (up-regulation of KCNA5 and KCNN3 and down-regulation of KCNJ8, KCNK1, and KCNJ5), and contraction (down-regulation of MYH6). Fibrosis-related genes showed the highest magnitude increased expression in arrhythmic vs nonarrhythmic deaths and vs published transcriptomes from end-stage heart failure. After molecular stratification by known markers for mature (COL1A1, COL1A2, COL3A1) and active (POSTN, MEOX1) fibrosis, cases with the highest expression of both had the largest proportion of arrhythmic cause of death (n = 27 of 36 [75%]) vs cases with low expression of both markers (n = 87 of 181 [38%]) (P = 0.006) or vs mature only (n = 10 of 14 [71%]) or active only (n = 5 of 14 [36%]). Activated fibroblast gene expression signature was enriched in arrhythmic female vs arrhythmic male cases, among other sex-specific differences in ion-channel and myosin (up-regulation of SCN4B, SCN8A, and KCNAB1 in females and KCNJ4 and MYH7B in males) expression.CONCLUSIONSRNA profiling of the myocardium at SCD identifies active fibrosis, undetectable by conventional clinical methods, in the presence of fixed scar and selected ion-channel dysregulation (more pronounced among female cases) as an acute vulnerable substrate for fatal arrhythmias. These findings may represent novel directions to identify patients at elevated near-term risk for SCD and critical pathways for intervention to reduce acute lethal arrhythmias.

31 Dec 2024·Channels

Characterization of four structurally diverse inhibitors of SUR2-containing K _ATP channels

Article

Author: Li, Kangjun ; Denton, Jerod ; 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.

01 Dec 2024·American Journal of Medical Genetics Part A

A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1

Article

Author: Tryon, Rob ; Gao, Jian ; Ververi, Athina ; Grange, Dorothy K. ; Nichols, Colin G. ; Giannios, Christos ; Sotiriadis, Alexandros ; Thompson, Ellen ; Rouvalis, Fotios

AbstractCantu syndrome (CS) (OMIM #239850) is an autosomal dominant multiorgan system condition, associated with a characteristic facial phenotype, hypertrichosis, and multiple cardiovascular complications. CS is caused by gain‐of‐function (GOF) variants in KCNJ8 or ABCC9 that encode pore‐forming Kir6.1 and regulatory SUR2 subunits of ATP‐sensitive potassium (KATP) channels. A novel heterozygous ABCC9 variant, c.2440G>T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside‐out patch‐clamp assays of KATP channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP‐binding cassette (ABC) protein ion channels.

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KCNJ8

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