Regulation of BK Channels by Beta and Gamma Subunits

González-Pérez, Vivian; Lingle, Christopher J.

doi:10.1146/annurev-physiol-022516-034038

Cited by 111 publications

(120 citation statements)

References 167 publications

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“…TRPV4 activation increases epithelial permeability in the mouse mammary cell line HC11, and this is prevented by the BK channel blocker paxilline in the early phase [7]. We have not demonstrated the expression of BK channels in MDCK II cells, but they are known to be expressed in epithelial cells of the kidney and in C11-MDCK cells [22,34]. However, we observed no inhibition of GSK-induced TJ opening by paxilline.…”

Section: Discussionmentioning

confidence: 64%

Transient receptor potential V4 channel stimulation induces reversible epithelial cell permeability in MDCK cell monolayers

et al. 2019

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The transient receptor potential V4 channel (TRPV4) is responsive to a variety of physical and chemical stimuli, including a synthetic agonist GSK1016790A (GSK). Here, we show that TRPV4 is functionally expressed in, and that GSK induces the reversible opening of tight junctions (TJs) in epithelial Madin–Darby canine kidney II monolayers. Stimulation of TRPV4 by GSK induces an increase in fluorescein isothiocyanate‐conjugated dextran (4 kDa) permeability and a reduction in transepithelial resistance, and these responses are blocked by pretreatment with the specific TRPV4 antagonist. Small conductance, but not large conductance Ca2+‐activated K+ channels, TRPA1 channel, and cofilin activation are involved in TRPV4‐mediated reversible opening of TJs. These results suggest that a novel mechanism underlies TRPV4‐mediated regulation of the tightness of epithelial barriers.

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Section: Discussionmentioning

confidence: 64%

Transient receptor potential V4 channel stimulation induces reversible epithelial cell permeability in MDCK cell monolayers

et al. 2019

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“…Different tissues exhibit BK currents of varying voltage and Ca 2+ -dependent activation properties, underlying the complex roles for BK channels in regulating excitability. This cell and tissue-specific regulation is achieved via extensive alternative splicing of KCNMA1 transcripts, assembly with modulatory βand γ-regulatory subunits, and a variety of post-translational modifications (Kyle and Braun, 2014;Latorre et al, 2017;Gonzalez-Perez and Lingle, 2019). These mechanisms work together to tailor the voltage and Ca 2+ dependence of channel activation, as well as the kinetics of activation and deactivation gating, for the cell-specific function of BK channels in excitability or K + transport.…”

Section: Bk Channel Structurementioning

confidence: 99%

KCNMA1-linked channelopathy

Bailey

Moldenhauer

Park

et al. 2019

Journal of General Physiology

117

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KCNMA1 encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1−/−) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as “KCNMA1-linked channelopathy.” These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

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“…However, important physiological properties of BK channels including their voltage and Ca 2+ -sensitivity depend on one-to-one co-assembly of the four BKα subunits with four regulatory BKβ subunits, which can include one of four isoforms (BKβ1, β2, β3, β4). Considering that different BKβ isoforms can profoundly impact the BK channel phenotype, including cellular localization and electrophysiological properties such as voltage sensitivity, Ca 2+ sensitivity, and inactivation kinetics [40], an important next step would be to identify the precise BKβ isoform(s) that regulate mitoBK channels in renal tubular cells. Recently, a study utilizing BKβ1-KO mice reported that the BKβ1 isoform regulates mitoBK channels and is required for its mitochondrial localization and activation in cardiomyocytes [41].…”

Section: Nrk Cells Express Mitobk Channelsmentioning

confidence: 99%

Specific BK Channel Activator NS11021 Protects Rat Renal Proximal Tubular Cells from Cold Storage—Induced Mitochondrial Injury In Vitro

2019

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Kidneys from deceased donors used for transplantation are placed in cold storage (CS) solution during the search for a matched recipient. However, CS causes mitochondrial injury, which may exacerbate renal graft dysfunction. Here, we explored whether adding NS11021, an activator of the mitochondrial big-conductance calcium-activated K+ (mitoBK) channel, to CS solution can mitigate CS-induced mitochondrial injury. We used normal rat kidney proximal tubular epithelial (NRK) cells as an in vitro model of renal cold storage (18 h) and rewarming (2 h) (CS + RW). Western blots detected the pore-forming α subunit of the BK channel in mitochondrial fractions from NRK cells. The fluorescent K+-binding probe, PBFI-AM, revealed that isolated mitochondria from NRK cells exhibited mitoBK-mediated K+ uptake, which was impaired ~70% in NRK cells subjected to CS + RW compared to control NRK cells maintained at 37 °C. Importantly, the addition of 1 μM NS11021 to CS solution prevented CS + RW-induced impairment of mitoBK-mediated K+ uptake. The NS11021–treated NRK cells also exhibited less cell death and mitochondrial injury after CS + RW, including mitigated mitochondrial respiratory dysfunction, depolarization, and superoxide production. In summary, these new data show for the first time that mitoBK channels may represent a therapeutic target to prevent renal CS-induced injury.

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Regulation of BK Channels by Beta and Gamma Subunits

Cited by 111 publications

References 167 publications

Transient receptor potential V4 channel stimulation induces reversible epithelial cell permeability in MDCK cell monolayers

Transient receptor potential V4 channel stimulation induces reversible epithelial cell permeability in MDCK cell monolayers

KCNMA1-linked channelopathy

Specific BK Channel Activator NS11021 Protects Rat Renal Proximal Tubular Cells from Cold Storage—Induced Mitochondrial Injury In Vitro

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