Potential Benefit of Channel Activators in Loss-of-Function Primary Potassium Channelopathies Causing Heredoataxia

Gazulla, José; Berciano, José

doi:10.1007/s12311-023-01584-8

Cited by 2 publications

(2 citation statements)

References 38 publications

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“…Voltage-gated potassium channels are transmembrane channels responsible for returning the depolarized cell to a resting state after an action potential (Gazulla and Berciano, 2023). Therefore, K V channels are important modulating neuronal excitability in the CNS, but also participate regulating other organs function.…”

Section: K V Channelsmentioning

confidence: 99%

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

Urrutia,

Arrizabalaga-Iriondo,

Sanchez-del-Rey

et al. 2024

Front. Cell. Neurosci.

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Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson’s Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets.

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Section: K V Channelsmentioning

confidence: 99%

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

Urrutia,

Arrizabalaga-Iriondo,

Sanchez-del-Rey

et al. 2024

Front. Cell. Neurosci.

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“…Generation rather than screening, were employed in this work to search for new anti-KcsA ligand candidates using the DataWarrior Build Evolutionary Library (DW-BEL) algorithms [2][3][4][5] . Starting from defined parent molecules and their preliminarily identified docking cavity, DW-BEL co-evolution generated tens of thousands raw children and thousands of highly specific cavityfitting children molecules [2][3][4][5]32 selected by their docking affinities. Despite the particular toxicity and/or steric difficulties found when targeting the known KcsA central cavity and/or lipid surfaces, respectively, the random generation of children molecules was very successful.…”

Section: Introductionmentioning

confidence: 99%

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

coll

2024

Preprint

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Human potassium channels (Kir) are implicated in numerous dysfunction diseases genetically affecting cardiovascular, skeletal-muscle and/or synaptic-neuronal functions. Variations in Kir sequences, organ distribution differences and toxicity of some of their known inhibitors, require alternative drugs to interfere specifically with each human Kir molecular species. In this work, a prokaryotic asymmetric transmembrane homotetramer potassium (K+) channel protein highly homologous to Kirs has been used as their model. Computational methods combining molecular parent co-evolutions confirmed by consensus docking, were explored as possible prove-of-concept to generate rather than screen for numerous KcsA docking-ligands. The explorations of the KcsA central cavity and of their interface lipid-binding shallow-grooves, predicted highly specific novel scaffolds with low-toxicity risks, displaying hundreds of molecular variations of new scaffolds within nanoMolar-ranged affinities. Experimental validation and/or additional computational research on human Kirs could be attempted in the future.

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Potential Benefit of Channel Activators in Loss-of-Function Primary Potassium Channelopathies Causing Heredoataxia

Cited by 2 publications

References 38 publications

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

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