Last update 01 Nov 2024

Kir6.2

Last update 01 Nov 2024

Basic Info

Synonyms

ATP-sensitive inward rectifier potassium channel 11, beta-cell inward rectifier, BIR

+ [7]

Introduction

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

Drugs associated with Kir6.2

Glyburide

Target

Kir6.2 x SUR1

Mechanism

Kir6.2 agonists [+1]

Active Org.

Ammtek Ltd. [+3]

Originator Org.

Pfizer Inc.

Active Indication

Inactive Indication

Brain Contusion [+7]

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date01 Jan 1981

Minoxidil

Target

ABCC9 x Kir6.2

Mechanism

ABCC9 agonists [+1]

Active Org.

JOHNSON AND JOHNSON GROUP CONSUMER COMPANIES [+4]

Originator Org.

Pfizer Inc.

Active Indication

Hypertension [+4]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date18 Oct 1979

Tolbutamide

Target

Kir6.2 x SUR1

Mechanism

Kir6.2 agonists [+1]

Active Org.

Changzhou Pharmaceutical Factory Co., Ltd.

Originator Org.

Pharmacia & Upjohn, Inc.

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date31 May 1957

263

Clinical Trials associated with Kir6.2

NCT06589141 / Not yet recruitingNot ApplicableIIT

Comparison Between Metformin and Glyburide in the Management of Gestational Diabetes: a Randomized Controlled Trial (GDM-MERGE Trial)

This study aims to compare the maternal, fetal, and neonatal outcomes associated with the use of metformin versus glyburide for managing gestational diabetes.
The objective is to assess the safety and effectiveness profiles of both medications as potential alternatives to initiating insulin therapy.

Start Date01 Jan 2025

Sponsor / Collaborator

Assiut University

ChiCTR2400088536 / SuspendedIIT

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

Start Date31 Oct 2024

Sponsor / Collaborator

China-Japan Friendship Hospital

CTRI/2024/10/074861 / Not yet recruitingNot Applicable

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

Start Date15 Oct 2024

Sponsor / Collaborator

Cipla Ltd.

100 Clinical Results associated with Kir6.2

100 Translational Medicine associated with Kir6.2

0 Patents (Medical) associated with Kir6.2

2,525

Literatures (Medical) associated with Kir6.2

01 Dec 2024·Molecular Biology Reports

Potential pathogenetic role of a novel ABCC8 missense variant on both transient neonatal diabetes mellitus and fetal growth restriction: a case report

Article

Author: Pitocco, Dario ; Fattore, Simona ; Minucci, Angelo ; Barbetti, Fabrizio ; Rinelli, Martina ; Vento, Giovanni ; Costa, Simonetta ; Perri, Alessandro

BACKGROUNDThe diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin production and secretion; low birthweight infants may have a reduced response to insulin. We report a novel missense ABCC8 variant associated with a clinical phenotype compatible with transient neonatal diabetes mellitus (TNDM) in a fetal growth restricted preterm infant.METHODS AND RESULTSA preterm growth restricted infant experienced hyperglycemia from the first day of life, requiring insulin therapy on the 13th and 15th day of life and leading to the diagnosis of TNDM. Glycemic values normalized from the 35th day of life onwards. Genetic screening was performed by next generation sequencing, using a Clinical Exon panel of 4800 genes, filtered for those associated with the clinical presentation and by means of methylation-specific multiplex ligation-dependent probe amplification analysis to identify chromosomal aberrations at 6q24. Genetic tests excluded defects at 6q24 and were negative for KCNJ11, SLC2A2 (GLUT-2) and HNF1B, but revealed the presence of the heterozygous missense variant c.2959T > C (p.Ser987Pro) in ABCC8 gene. The presence of the variant was excluded in parents' DNA and the proband variant was then considered de novo.CONCLUSIONSIn our infant, the persistence of hyperglycemia beyond 3 weeks of life led us to the diagnosis of TNDM and to hypothesize a possible genetic cause. The genetic variant we found could be, most likely, the main cause of both FGR and TNDM.

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.

01 Nov 2024·Clinical Endocrinology

Phenotypic features, prevalence of KCNJ11‐MODY in Chinese patients with early‐onset diabetes and a literature review

Review

Author: Liu, Wei ; Zhou, Lingli ; Zhang, Simin ; Cai, Xiaoling ; Ba, Tianhao ; Zhang, Xiuying ; Chen, Jing ; Luo, Yingying ; Gong, Siqian ; Li, Yufeng ; Zhong, Liyong ; Zhou, Xianghai ; Wang, Fang ; Han, Xueyao ; Zhu, Yu ; Wu, Jing ; Wang, Xirui ; Ren, Qian ; Li, Meng ; Ji, Linong ; Zhang, Rui

AbstractObjectiveGain‐of‐function (GOF) variants of KCNJ11 cause neonate diabetes and maturity‐onset diabetes of the young (KCNJ11‐MODY), while loss‐of‐function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11‐MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early‐onset type 2 diabetes (EOD).Design, Patients and MeasurementsWe performed next‐generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11‐MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11‐MODY.ResultsWe identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11‐MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C‐peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed.ConclusionsSome rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11‐MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11‐MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

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Kir6.2

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