Last update 19 Sep 2024

SLC12A4

Last update 19 Sep 2024

Basic Info

Synonyms

Electroneutral potassium-chloride cotransporter 1, Erythroid K-Cl cotransporter 1, hKCC1

+ [4]

Introduction

Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (PubMed:10913127, PubMed:34031912). May be involved in the regulation of basolateral Cl(-) exit in NaCl absorbing epithelia (By similarity). No transporter activity.

Drugs associated with SLC12A4

Bumetanide

Target

NKCC1 x NKCC2 x SLC12A4

Mechanism

NKCC1 inhibitors [+2]

Active Org.

Guilin Pharmaceutical Group Co., Ltd. [+4]

Originator Org.

Daiichi Sankyo Co., Ltd.

Active Indication

Heart Failure [+6]

Inactive Indication

Autism Spectrum Disorder

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date08 Apr 1976

Clinical Trials associated with SLC12A4

CTR20240307 / CompletedNot Applicable

中国健康受试者单次口服布美他尼片（1mg）的开放、随机、单剂量、两制剂、单次给药、交叉设计的生物等效性试验

[Translation] An open-label, randomized, single-dose, two-formulation, single-dose, crossover-design bioequivalence study of a single oral dose of bumetanide tablets (1 mg) in healthy Chinese subjects

主要研究目的研究空腹和餐后单次口服布美他尼片受试制剂（规格：1mg，新乡市常乐制药有限责任公司生产，浙江和沐康医药科技有限公司提供）与布美他尼片参比制剂（Burinex®，规格：1mg，Karo Pharma AB持证，浙江和沐康医药科技有限公司提供）在中国健康受试者体内的药代动力学行为，评价空腹及餐后口服两种制剂的生物等效性。次要研究目的评价中国健康受试者空腹和餐后单次口服受试制剂（T）布美他尼片和参比制剂（R）布美他尼片（Burinex®）后的安全性。

[Translation]

Main study objectives To study the pharmacokinetic behavior of the test formulation of bumetanide tablets (specification: 1 mg, produced by Xinxiang Changle Pharmaceutical Co., Ltd., provided by Zhejiang Hemukang Pharmaceutical Technology Co., Ltd.) and the reference formulation of bumetanide tablets (Burinex®, specification: 1 mg, licensed by Karo Pharma AB, provided by Zhejiang Hemukang Pharmaceutical Technology Co., Ltd.) in Chinese healthy subjects after single oral administration on an empty stomach and after a meal, and to evaluate the bioequivalence of the two formulations after oral administration on an empty stomach and after a meal. Secondary study objectives To evaluate the safety of the test formulation (T) bumetanide tablets and the reference formulation (R) bumetanide tablets (Burinex®) after single oral administration on an empty stomach and after a meal in Chinese healthy subjects.

Start Date27 Feb 2024

Sponsor / Collaborator

Zhejiang Hemukang Pharmaceutical Technology Co., Ltd.

NCT06036914 / Enrolling by invitationPhase 2

Ultra High Dose Diuretic Strategy for Management of Acute Decompensated Heart Failure - A Randomized, Double-Blind Pilot Trial

The purpose of this study is to determine the safety and effectiveness of ultrahigh dose diuretics compared to standard dose diuretics over 24 hours in patients with decompensated heart failure.

Start Date27 Nov 2023

Sponsor / Collaborator

Mayo Clinic

NCT06052163 / RecruitingPhase 2IIT

Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Tolerability of Bumetanide in Patients With Alzheimer's Disease.

This study aims to investigate bumetanide in patients with biologically confirmed Alzheimer's disease (AD). Bumetanide is a potent diuretic administered orally and is FDA approved for the treatment of edema and hypertension. Repurposing bumetanide as a medication for AD has been proposed based on data that demonstrated its ability to "flip" the APOE genotype-dependent transcriptomic signatures in AD mouse and cell culture models. Critically, this discovery was subsequently explored in Electronic Health Record cohorts, which revealed that among individuals over the age of 65, bumetanide exposure was significantly associated with a lower prevalence of AD in three independent datasets.
Primary Objective: To evaluate the safety and tolerability of bumetanide when administered to participants with biomarker-confirmed Alzheimer's disease.
Secondary Objective: To evaluate the clinical and biomarker effects of bumetanide in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.

Start Date10 Apr 2023

Sponsor / Collaborator

Stanford University

100 Clinical Results associated with SLC12A4

100 Translational Medicine associated with SLC12A4

0 Patents (Medical) associated with SLC12A4

173

Literatures (Medical) associated with SLC12A4

01 Sep 2024·Animal Bioscience

Genome-wide association research on the reproductive traits of Qianhua Mutton Merino sheep

Article

Author: Li, Jiarong ; Sun, Jiazhi ; Sun, Limin ; Jiang, Huaizhi

Objective: Qianhua Mutton Merino sheep is a new breed of meat wool sheep cultivated independently in China. In 2018, it was approved by the state and brought into the national list of livestock and poultry genetic resources. Qianhua Mutton Merino sheep have the common characteristics of typical meat livestock varieties with rapid growth and development in the early stage and high meat production performance. The objective of this research is to investigate the Genome-wide association of the reproductive traits of Qianhua Mutton Merino sheep.Methods: Qianhua Mutton Merino sheep from the breeding core group were selected as the research object, genome-wide association analysis was conducted on genes associated with the reproductive traits (singleton or twins, birth weight, age [in days] for sexual maturity, weaning weight, and daily gain from birth to weaning) of Qianhua mutton merino.Results: Our study findings showed that 151 loci of single-nucleotide polymorphisms (SNPs) were detected, among which 3 SNPs related to birth weight and weaning weight occupied a significant portion of the wide genome. The candidate genes preliminarily obtained were <i>SYNE1, SLC12A4, BMP2K, CAMK2D, IMMP2L, DMD,</i> and <i>BCL2</i>.Conclusion: We found 151 SNP loci for five traits related to reproduction (including singleton or twins, birth weight, age [in days] at sexual maturity, weaning weight, and daily weight gain from birth to weaning). The functions of these candidate genes were mainly enriched in nucleotide metabolism, metal ion binding, oxytocin signaling pathway, and neurotrophin signaling pathway.

01 Jul 2024·Acta Pharmaceutica Sinica B

Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice

Article

Author: Zhou, Hongwei ; Wan, Yantong ; Hong, Yinghao ; Zhang, Xianglong ; Gong, Shenhai ; Chen, Peng ; Zeng, Zhenhua ; Gu, Peng ; Wang, Fangzhao ; Li, Jiaxin ; Jiang, Yong ; Li, Dongping ; Wan, Meijuan ; Chen, Meiling ; Liu, Ruofan ; Selva Nandakumar, Kutty ; Wei, Rongjuan ; Wang, Zhang

Sepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with l-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.

01 Dec 2023·Journal of Pharmaceutical Analysis

The role of SLC12A family of cation-chloride cotransporters and drug discovery methodologies

Review

Author: Dai, Cuilian ; Zhou, Xiaoxia ; Li, Zhengqiu ; Liang, Dong ; Wang, Yan ; Meor Azlan, Nur Farah ; Josiah, Sunday Solomon ; Wang, Yun ; Li, Peifeng ; Zhang, Shiyao ; Wang, Zhen ; Zhang, Jinwei ; Ding, Ke ; Jie, Lingjun ; Zhang, Yanhui ; Zhou, Jing

The solute carrier family 12 (SLC12) of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl^- extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl^- loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs. Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs. These techniques include the ammonium pulse technique, radioactive or nonradioactive rubidium ion uptake-assay, and thallium ion-uptake assay. CCCs' activity can also be indirectly observed by measuring γ-aminobutyric acid (GABA) activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes, radiotracer ³⁶Cl^-, and fluorescent dyes. Other techniques include directly looking at kinase regulatory sites phosphorylation, flame photometry, ²²Na⁺ uptake assay, structural biology, molecular modeling, and high-throughput drug screening. This review summarizes the role of CCCs in genetic disorders and cell volume regulation, current methods applied in studying CCCs biology, and compounds developed that directly or indirectly target the CCCs for disease treatments.

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SLC12A4

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