更新于：2024-11-01

KCNJ1

更新于：2024-11-01

基本信息

别名

ATP-regulated potassium channel ROM-K、ATP-sensitive inward rectifier potassium channel 1、Inward rectifier K(+) channel Kir1.1

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简介

In the kidney, probably plays a major role in potassium homeostasis. 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. This channel is activated by internal ATP and can be blocked by external barium.

关联

项与 KCNJ1 相关的药物

VU591

靶点

KCNJ1

作用机制

KCNJ1抑制剂

在研机构

Vanderbilt University

原研机构

Vanderbilt University

在研适应症

低钾血症

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

MK-7145

靶点

KCNJ1

作用机制

KCNJ1抑制剂

在研机构-

原研机构

Merck Sharp & Dohme Corp.

在研适应症-

非在研适应症

心脏衰竭 [+2]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

BMS-986308

靶点

KCNJ1

作用机制

KCNJ1抑制剂

在研机构-

原研机构

Bristol Myers Squibb Co.

在研适应症-

非在研适应症

心脏衰竭

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 KCNJ1 相关的临床试验

NCT04763226 / Completed临床1期

A Randomized, Double-Blinded, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-986308 in Healthy Participants

The purpose of this study is to evaluate the safety, tolerability, drug levels, and drug effects of BMS-986308 compared to placebo in healthy participants.

开始日期2021-04-14

申办/合作机构

Bristol Myers Squibb Co.

NCT03971929 / Completed临床1期

A Phase I, Randomized, Double-Blind, Placebo-hydrochlorothiazide Parallel Controlled, Multiple-Ascending Dose Study to Evaluate the Safety, Efficacy of SHR 0532 Oral Tablets in Mild Hypertension Subjects

The study is being conducted to evaluate the safety and efficacy and Pharmacokinetics/Pharmacodynamics of SHR0532 in subjects with mild hypertension for 4 weeks.

开始日期2019-07-31

申办/合作机构

江苏恒瑞医药股份有限公司

CTR20191054 / Completed临床1期

多次服SHR0532片在轻度高血压患者的安全性和有效性研究—随机、双盲、剂量递增、安慰剂和氢氯噻嗪平行对照Ⅰ期试验

主要目的：多次口服SHR0532片后在轻度高血压患者中的安全性。次要目的：多次口服SHR0532片后在轻度高血压患者中的SHR0532的药代动力学（PK）和药效动力学（PD）特征。

开始日期2019-07-25

申办/合作机构

上海恒瑞医药有限公司

[+1]

100 项与 KCNJ1 相关的临床结果

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100 项与 KCNJ1 相关的转化医学

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0 项与 KCNJ1 相关的专利（医药）

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645

项与 KCNJ1 相关的文献（医药）

2024-12-31·Channels

A phenylalanine at the extracellular side of Kir1.1 facilitates potassium permeation

Article

作者: Nanazashvili, Mikheil ; Sackin, Henry

The Kir1.1 (ROMK) family of weak inward rectifiers controls K secretion in the renal CCT and K recycling in the renal TALH. A single point mutant of the inward rectifier, F127V-Kir1.1b was used to investigate the K transition between the selectivity filter and the outer mouth of the channel. We hypothesize that normally an aromatic Phe at the external entryway of Kir1.1b facilitates outward K secretion. We tested this by replacing F127-Kir1.1b with a small aliphatic Val. Results indicate that removal of the Phe at 127 suppresses outward currents that normally contribute to K secretion. Results with the F127V mutant could be explained by increased polyamine block and/or a decrease in the avidity of Kir1.1 for K ions near the outer mouth of the channel. The latter is supported by F127V-Kir1.1b having a lower affinity (K_m = 33 mM) for K than wild-type Kir1.1b (K_m = 7 mM) during external K elevation. Conversely, chelation of K with 18-Crown-6 ether reduced K conductance faster in F127V (half-time = 6s) than in wt-Kir1.1b (half-time = 120s), implying that F127V is less hospitable to external K. In other experiments, positive membrane potentials gated the F127V mutant channel closed at physiological levels of external Ca, possibly by electrostatically depleting K adjacent to the membrane, suggesting that the Phe residue is critical for outward K secretion at physiological Ca. We speculate that the avidity of wt-Kir1.1b for external K could result from a cation-Pi interaction between K and the aromatic F127.

2024-09-01·Hypertension Research

Mechanistic study on vasodilatory and antihypertensive effects of hesperetin: ex vivo and in vivo approaches

Article

作者: Yan, Chong Seng ; Wei, Xu ; Tan, Chu Shan ; Loh, Hui Wei ; Wen, Xu ; Wang, Xuye ; Yam, Mun Fei ; Tew, Wan Yin

Hesperetin is one of the prominent flavonoids found in citrus fruit. Several research studies have reported that hesperetin can promote vasodilation in vascular tissue by increasing the level of nitric oxide and cyclic nucleotides. However, these may not be the only pathway for hesperetin to exert its vasodilatory effect. In addition to vasodilation, hesperetin has been found to carry an antihypertensive effect through intraperitoneal injection, although no study has comprehensively investigated the antihypertensive effect of hesperetin through oral administration. Therefore, this study aimed to determine the possible mechanism pathways involved in hesperetin-induced vasodilation and investigated its antihypertensive effects on hypertensive rats' model via oral administration. The ex vivo experimental findings showed that the NO/sGC/cGMP signalling pathway was involved in hesperetin-mediated vasodilation. Moreover, hesperetin activated the AC/cAMP/PKA pathway through PGI₂ and activated the β₂-adrenergic receptor. Hesperetin can act as a voltage-gated potassium channel (K_V) and ATP-sensitive potassium channel (K_ATP) opener. The intracellular calcium in vascular smooth muscle was reduced by hesperetin through blocking the voltage-operated calcium channels (VOCC) and inositol triphosphate receptor (IP₃R). In the in vivo assessment, hesperetin shows a significant decrease in Spontaneously Hypertensive rats' blood pressure following 21 days of oral treatment. The sub-chronic toxicity assessment demonstrated that hesperetin exhibited no deleterious effects on the body weights, clinical biochemistry and haematological profile of Sprague-Dawley rats. This study implies that hesperetin holds promise as a potential medication for hypertension treatment, devoid of undesirable side effects.

2024-09-01·Journal of the American Society of Nephrology

mTORc2 in Distal Convoluted Tubule and Renal K+ Excretion during High Dietary K+ Intake

Article

作者: Zheng, Jun-Ya ; Duan, Xin-Peng ; Lin, Dao-Hong ; Wang, Ming-Xiao ; Chowdhury, Tanzina ; Zhang, Chengbiao ; Wang, Wen-Hui ; Jiang, Shao-Peng

Key Points

High K stimulates mechanistic target of rapamycin complex 2 (mTORc2) in the distal convoluted tubule (DCT).

Inhibition of mTORc2 decreased the basolateral Kir4.1/Kir5.1 and Na-Cl cotransporter in the DCT.

Inhibition of mTORc2 of the DCT compromised kidneys' ability to excrete potassium during high K intake.

BackgroundRenal mechanistic target of rapamycin complex 2 (mTORc2) plays a role in regulating renal K+ excretion (renal-EK) and K+ homeostasis. Inhibition of renal mTORc2 causes hyperkalemia due to suppressing epithelial Na+ channel and renal outer medullary K+ (Kir1.1) in the collecting duct. We now explore whether mTORc2 of distal convoluted tubules (DCTs) regulates basolateral Kir4.1/Kir5.1, Na-Cl cotransporter (NCC), and renal-EK.MethodsWe used patch-clamp technique to examine basolateral Kir4.1/Kir5.1 in early DCT, immunoblotting, and immunofluorescence to examine NCC expression and in vivo measurement of urinary K+ excretion to determine baseline renal-EK in mice treated with an mTORc2 inhibitor and in DCT-specific rapamycin-insensitive companion of mTOR knockout (DCT-RICTOR-KO) mice.ResultsInhibition of mTORc2 with AZD8055 abolished high-K+–induced inhibition of Kir4.1/Kir5.1 in DCT, high potassium–induced depolarization of the DCT membrane, and high potassium–induced suppression of phosphorylated Na-Cl cotransporter (pNCC) expression. AZD8055 stimulated the 40-pS inwardly rectifying K+ channel (Kir4.1/Kir5.1-heterotetramer) in early DCT in the mice on overnight high potassium intake; this effect was absent in the presence of protein kinase C inhibitors, which also stimulated Kir4.1/Kir5.1. AZD8055 treatment decreased renal-EK in animals on overnight high-potassium diet. Deletion of RICTOR in the DCT increased the Kir4.1/Kir5.1-mediated K+ currents, hyperpolarized the DCT membrane, and increased the expression of pWNK4 and pNCC. Renal-EK was lower and plasma K+ was higher in DCT-RICTOR-KO mice than corresponding control mice. In addition, overnight high-potassium diet did not inhibit Kir4.1/Kir5.1 activity in the DCT and failed to inhibit the expression of pNCC in DCT-RICTOR-KO mice. Overnight high potassium intake stimulated renal-EK in control mice, but this effect was attenuated in DCT-RICTOR-KO mice. Thus, overnight high potassium intake induced hyperkalemia in DCT-RICTOR-KO mice but not in control mice.ConclusionsmTORc2 of the DCT inhibits Kir4.1/Kir5.1 activity and NCC expression and stimulates renal-EK during high potassium intake.