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Last update 23 Jan 2025

Kir4.1

Last update 23 Jan 2025

Basic Info

Synonyms

ATP-dependent inwardly rectifying potassium channel Kir4.1, ATP-sensitive inward rectifier potassium channel 10, Inward rectifier K(+) channel Kir1.2

+ [6]

Introduction

May be responsible for potassium buffering action of glial cells in the brain. 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 and cesium (By similarity). In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules.

Drugs associated with Kir4.1

VU0134992

Target

Kir4.1

Mechanism

Kir4.1 inhibitors

Active Org.

Vanderbilt University

Originator Org.

Vanderbilt University

Active Indication

Hypertension

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

VU6036720

Target

Kir4.1 x Kir5.1

Mechanism

Kir4.1 inhibitors [+1]

Active Org.

Vanderbilt University

Originator Org.

Vanderbilt University

Active Indication

Edema [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Kir4.1

100 Translational Medicine associated with Kir4.1

0 Patents (Medical) associated with Kir4.1

825

Literatures (Medical) associated with Kir4.1

01 Feb 2025·European Journal of Pharmacology

Pore blocking mechanisms of centipede toxin SsTx-4 on the inwardly rectifying potassium channels

Article

Author: Tang, Cheng ; Rong, Mingqiang ; Liu, Zhonghua ; Luo, Xiaofang ; Xu, Fanping ; Tan, Zheni ; Li, Chuanli ; Qi, Jieqiong ; Bao, Wenhu ; Tang, Dongfang ; You, Xia ; Xu, Jiahui

The peptide toxin SsTx-4 derived from venom of centipede Scolopendra subspinipes mutilans was characterized as a potent antagonist of the inwardly rectifying potassium (Kir) channel subtypes Kir1.1, Kir4.1, and Kir6.2 in our previous study. Alanine-scanning mutagenesis analysis identified key molecular determinants on the SsTx-4 toxin interacting with these Kir channels, as well as those on the Kir6.2 channel interacting with the toxin. However, the key residues on Kir1.1 and Kir4.1 channels responsible for binding SsTx-4 remain unclear. Here, using a combination of site-directed mutagenesis, patch-clamp analysis, molecular docking with AlphaFold 3, and molecular dynamic simulations, we revealed that SsTx-4 acted on the Kir channels as a pore blocker, with K13 on toxin serving as the functional pore-blocking residue and other residues on it contributing to stabilize the toxin-channel complex by binding to multiple residues on the wall of the channels' outer vestibule, involving E104 on Kir1.1; D100, L115, and F133 on Kir4.1; and E108, S113, H115, and M137 on Kir6.2. Collectively, these findings advanced our understanding on the interaction between Kir channels and this prototype Kir antagonist, providing insights that could inspire the development of more potent and specific Kir subtype blockers in the future.

01 Jan 2025·Neuroscience

Adolescent seizure impacts oligodendrocyte maturation, neuronal-glial circuit Formation, and myelination in the mammalian forebrain

Article

Author: Baldemor, Megan ; Lokhandwala, Mariyam ; Franzia, Chloe ; Brock, Robert ; Cooney, Aundrea ; Tilton, Iris ; Bender, Cole ; Noguchi, Hirofumi ; Cocas, Laura ; Arellano Reyes, Christopher ; Foutch, Kylie ; Licharz, Collin ; Garcia, Mary Francis ; Asal Sahagun, Atehsa ; Moura, Daniela ; Rock, Caitlyn ; Gupta, Raghav

Oligodendrocyte progenitor cells differentiate into oligodendrocytes, which myelinate axons during development and following demyelinating injury. However, the mechanisms that drive the timing and specificity of developmental myelination are not well understood. We hypothesized that oligodendrocyte progenitor cell proliferation and differentiation would be affected by pathological neuronal activity during adolescent development when developmental myelination is occurring and that this would also impact neuron-to-oligodendrocyte progenitor cell connectivity and myelination. We used kainic acid to induce a seizure in mice, treating equal numbers of males and females, in sample sizes of at least five animals. We found that the seizures led to increased cell death overall, specifically in the oligodendrocyte-lineage cells. We found that both oligodendrocyte progenitor cell proliferation and overall numbers increased, and the number of mature oligodendrocytes decreased. We found a decrease in myelin in the cerebral cortex, corpus callosum, and hippocampus after a seizure. We observed an increase in demyelinating lesions, but no change in neuronal process length, in brains after seizure, suggesting that the demyelination was due primarily to the loss of both oligodendrocyte-lineage cells. We found that Kir4.1 potassium channel expression on oligodendrocyte progenitor cells decreased after seizure, but not mature oligodendrocytes. Finally, we found a decrease in neuron-to-oligodendrocyte progenitor cell connections in seizure mice compared to controls. These findings provide insight into the response of the adolescent brain to seizure activity, as well as how seizures affect oligodendrocyte development, neuronal-glial connections, and myelin formation.

01 Jan 2025·Neurobiology of Disease

Astrocytic proteins involved in regulation of the extracellular environment are increased in the Alzheimer's disease middle temporal gyrus

Article

Author: Faull, Richard L M ; Tan, Adelie Y S ; Mehrabi, Nasim F ; Curtis, Maurice A ; Singh-Bains, Malvindar K ; Liu, Henry ; Dragunow, Mike ; Smith, Amy M ; Turner, Clinton P

Alzheimer's disease (AD) has complex pathophysiology involving numerous cell types and brain processes. Astrocyte involvement in AD is gaining increased attention, however a complete characterisation of astrocytic changes in the AD human brain is warranted. Astrocytes perform important homeostatic functions including regulation of the extracellular microenvironment, critical for the health of all brain cells. We have investigated changes to key astrocyte proteins involved in the regulation of CNS extracellular environment in the human AD middle temporal gyrus (MTG): aquaporin-4 (AQP-4), glutamate transporter-1 (GLT-1) and inwardly-rectifying potassium channel 4.1 (Kir4.1). We have used a high-throughput human brain tissue microarray platform with automated quantitative image analysis to measure protein changes in a large cohort of neurological control and AD cases. We found increased astrocytic glial acidic fibrillary protein (GFAP), AQP-4, GLT-1 and Kir4.1 expression that correlates with advancing Braak stage, increasing amyloid pathology and, to a greater extent, the degree of tau pathology. We confirmed that Kir4.1 immunostaining is predominantly found in astrocytes and revealed a novel redistribution of Kir4.1 protein expression into astrocytic processes in the AD MTG. Our study presents novel and potentially modifiable glial changes in the AD human brain that are critical to our understanding of disease pathogenesis.

News (Medical) associated with Kir4.1

07 Nov 2023

·www.biospace.com

Cerevance Announces Presentation at the SFN Neuroscience 2023 Annual Meeting

BOSTON, Nov. 07, 2023 (GLOBE NEWSWIRE) -- Cerevance, a company focused on developing novel precision therapeutics for central nervous system (CNS) diseases, today announced plans to present a poster presentation at the Neuroscience 2023 Annual Meeting presented by the Society for Neuroscience, taking place in Washington, D.C., November 11 – 15th, 2023. Presentation details Title: NETSseq platform identifies the astrocyte specific potassium channel KCNJ10 (kir4.1) as a target for the potential treatment of neurodegenerative diseases Overview: Gene expression relevant to human disease pathology can be observed using Cerevance’s proprietary NETSseq platform. Data from this approach demonstrated that KCNJ10 is expressed in astrocytes from post-mortem brain tissue of Alzheimer’s and Parkinson’s disease donors and is increased in disease. Given that KCNJ10 is a central hub of many pathways significantly impacted by CNS diseases, including glutamate uptake, targeting this gene may present a novel approach to preventing neuronal hyperexcitability in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Presenters: Clare Bender, Jenna Harvey Session and Date and Time: Potassium Channels; November 15th, 8am – 12pm ET Poster Number: C58 About Cerevance Cerevance is focused on the development of precision treatments for central nervous system (CNS) disorders, prioritizing chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). Utilizing a large and growing collection of over 14,000 human brain tissue samples, Cerevance is generating an unprecedented level of expression and epigenetic data thereby enabling the company to identify the most promising targets for the next generation of treatments for CNS disorders. The company utilizes its proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform and advanced machine learning techniques to uncover the gene expression profiles of select cell types to identify novel targets that are uniquely expressed in relevant circuits affected by diseases or are altered in disease states. With the information obtained from its research, combined with the expertise of its team of scientists and drug developers, Cerevance is advancing multiple therapeutics that selectively modulate the discovered targets. These treatments are progressing through clinical development, with CVN424, CVN766, and CVN293 being the furthest along in the pipeline. CVN424 is a first-in-class non-dopamine therapy that shows promise in improving both motor and non-motor symptoms of Parkinson's disease and may also have disease-delaying effects. CVN766 is a potent antagonist of the orexin 1 receptor with high selectivity over the orexin 2 receptor which may benefit a variety of psychiatric conditions including schizophrenia, anxiety/panic, binge eating/obesity, substance use disorder, and Prader-Willi Syndrome. CVN293 is a novel blocker of potassium efflux in glia, regulating the inflammasome in individuals living with ALS and Alzheimer's disease. By leveraging its extensive collection of brain tissue samples, employing advanced technologies, and generating actionable data, Cerevance aims to transform the lives of patients affected by CNS diseases. Contacts Cerevance: Johnna Simoes, ir@cerevance.com Media: Andrew Mielach, amielach@lifescicomms.com, +1-646-876-5868

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Kir4.1

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