Cholesterol activates BK channels by increasing KCNMB1 protein levels in the plasmalemma

Bukiya, Anna N.; Leo, M. Dennis; Jaggar, Jonathan H.; Dopico, Alex M.

doi:10.1016/j.jbc.2021.100381

Cited by 14 publications

(20 citation statements)

References 67 publications

(93 reference statements)

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“…Overall, this lack of effect of MβCD treatment on SK Ca /IK Ca channel function is consistent with previous studies (reviewed in [ 49 ]). As highly expressed in smooth muscle cells [ 50 ], large conductance K Ca (BK Ca ) channels are suppressed [ 51 ] or activated in response to membrane-enriched cholesterol depending on expression of KCNMB1 and trafficking of BK Ca β 1 subunits [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Methyl-Beta-Cyclodextrin Restores KIR Channel Function in Brain Endothelium of Female Alzheimer’s Disease Mice

Hakim

Behringer

2021

ADR

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Background: As the sixth-leading cause of death in the United States, Alzheimer’s disease (AD) entails deteriorating endothelial control of blood flow throughout the brain. In particular, reduced inward-rectifying K + (KIR) channel function in animal models of aging and AD compromises endothelial function and optimal perfusion of brain parenchyma. Deficient endothelial KIR channels may result from aberrant interaction with plasma membrane cholesterol as a primary regulator of membrane fluidity and ion channels. Objective: We tested the hypothesis that mild methyl-β-cyclodextrin (MβCD) treatment to reduce membrane cholesterol may restore endothelial KIR channel function in brain endothelium of old AD mice. Methods: Membrane potential was continuously measured in isolated endothelial tubes from posterior cerebral arteries of young (1 to 3 months) and old (16 to 19 months) female 3xTg-AD mice before and after mild treatment with the cholesterol-removing agent MβCD (1 mmol/L). Elevated extracellular potassium ([K +]E; 15 mmol/L) and NS309 (1μmol/L) activated KIR and Ca2 +-activated K + (SKCa/IKCa) channels respectively before and after MβCD treatment. Results: SKCa/IKCa channel function for producing hyperpolarization remained stable regardless of age group and MβCD treatment (ΔVm: ∼–33 mV). However, as deficient during AD, KIR channel function was restored (ΔVm: –9±1 mV) versus pre-MβCD conditions (–5±1 mV); a progressive effect that reached –14±1 mV hyperpolarization at 60 min following MβCD washout. Conclusion: In female animals, MβCD treatment of brain endothelium selectively restores KIR versus SKCa/IKCa channels function during AD. Thus, the endothelial cholesterol-KIR channel interface is a novel target for ameliorating perfusion of the AD brain.

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Section: Discussionmentioning

confidence: 99%

Methyl-Beta-Cyclodextrin Restores KIR Channel Function in Brain Endothelium of Female Alzheimer’s Disease Mice

Hakim

Behringer

2021

ADR

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“…Noteworthy, however, cholesterol down-regulates BK channels and its acute depletion using methyl-β-cyclodextrin potentiates channel activity ( Dopico and Bukiya, 2014 ). However, a recent study using native cerebral artery smooth muscle cells revealed that cholesterol enrichment stimulated BK channels, and this effect was driven by increases in cell membrane levels of β 1 subunits ( Bukiya et al, 2021 ). In support to these findings, smooth muscle cells isolated from human coronary atherosclerotic plaque samples exhibited significantly higher channel activity than those obtained from coronary media segments ( Wiecha et al, 1997 ).…”

Section: Pharmacology Of Bk Channelsmentioning

confidence: 99%

The Large-Conductance, Calcium-Activated Potassium Channel: A Big Key Regulator of Cell Physiology

Sancho

Kyle

2021

Front. Physiol.

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Large-conductance Ca2+-activated K+ channels facilitate the efflux of K+ ions from a variety of cells and tissues following channel activation. It is now recognized that BK channels undergo a wide range of pre- and post-translational modifications that can dramatically alter their properties and function. This has downstream consequences in affecting cell and tissue excitability, and therefore, function. While finding the “silver bullet” in terms of clinical therapy has remained elusive, ongoing research is providing an impressive range of viable candidate proteins and mechanisms that associate with and modulate BK channel activity, respectively. Here, we provide the hallmarks of BK channel structure and function generally, and discuss important milestones in the efforts to further elucidate the diverse properties of BK channels in its many forms.

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“…In research, randomly-methylated-β-cyclodextrin (MβCD) is most widely used due to its highest efficiency among CD derivatives to extract cholesterol from the cell membrane ( Szente and Fenyvesi, 2017 ; Szente et al, 2018 ). It is typically applied at 3–5 mM for 1 h for membrane cholesterol depletion, while MβCD previously complexed with cholesterol potently elevates membrane cholesterol levels ( Zidovetzki and Levitan, 2007 ; Bukiya et al, 2021 ). In clinical practice and in vivo experiments, hydroxypropyl-β-cyclodextrin (HPβCD) is the most commonly employed CD to deplete cholesterol due to its better safety profile compared to MβCD ( Irie and Uekama, 1997 ; Szente et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Cyclodextrins Exert a Ligand-like Current Inhibitory Effect on the KV1.3 Ion Channel Independent of Membrane Cholesterol Extraction

Kovács

Sohajda

Szente

et al. 2021

Front. Mol. Biosci.

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Cyclodextrins (CDs) are cyclic oligosaccharides capable of forming water-soluble complexes with a variety of otherwise poorly soluble molecules including cholesterol and different drugs. Consistently, CDs are widely used in research and clinical practice to deplete cholesterol from cellular membranes or to increase solubility and bioavailability of different pharmaceuticals at local concentrations in the millimolar range. Effects of CDs exerted on cellular functions are generally thought to originate from reductions in cholesterol levels. Potential direct, ligand-like CD effects are largely neglected in spite of several recent studies reporting direct interaction between CDs and proteins including AMP-activated protein kinase, β-amyloid peptides, and α-synuclein. In this study, by using patch-clamp technique, time-resolved quantitation of cholesterol levels and biophysical parameters and applying cholesterol-extracting and non-cholesterol-extracting CDs at 1 and 5 mM concentrations, we provide evidence for a previously unexplored ligand-like, cholesterol-independent current inhibitory effect of CDs on KV1.3, a prototypical voltage-gated potassium channel with pathophysiological relevance in various autoimmune and neurodegenerative disorders. Our findings propose that potential direct CD effects on KV channels should be taken into consideration when interpreting functional consequences of CD treatments in both research and clinical practice. Furthermore, current-blocking effects of CDs on KV channels at therapeutically relevant concentrations might contribute to additional beneficial or adverse effects during their therapeutic applications.

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Cholesterol activates BK channels by increasing KCNMB1 protein levels in the plasmalemma

Cited by 14 publications

References 67 publications

Methyl-Beta-Cyclodextrin Restores KIR Channel Function in Brain Endothelium of Female Alzheimer’s Disease Mice

Methyl-Beta-Cyclodextrin Restores KIR Channel Function in Brain Endothelium of Female Alzheimer’s Disease Mice

The Large-Conductance, Calcium-Activated Potassium Channel: A Big Key Regulator of Cell Physiology

Cyclodextrins Exert a Ligand-like Current Inhibitory Effect on the KV1.3 Ion Channel Independent of Membrane Cholesterol Extraction

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