Targeting potassium channels in cancer

Huang, Xi; Jan, Yuh Nung

doi:10.1085/jgp.1442oia34

Cited by 12 publications

(13 citation statements)

References 83 publications

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“…S8) and therefore the assay is easily scalable. Human genetic data point to K + channels as being likely targets for new therapies for asthma (9,11,13), hypertension (15,37), and perhaps even anticancer therapy (38). LFA can allow rapid screening for identifying new compounds that target K + channels.…”

Section: Discussionmentioning

confidence: 99%

Novel cell-free high-throughput screening method for pharmacological tools targeting K ⁺ channels

Brown

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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K+ channels, a superfamily of ∼80 members, control cell excitability, ion homeostasis, and many forms of cell signaling. Their malfunctions cause numerous diseases including neuronal disorders, cardiac arrhythmia, diabetes, and asthma. Here we present a novel liposome flux assay (LFA) that is applicable to most K+ channels. It is robust, low cost, and high throughput. Using LFA, we performed small molecule screens on three different K+ channels and identified new activators and inhibitors for biological research on channel function and for medicinal development. We further engineered a hERG (human ether-à-go-go-related gene) channel, which, when used in LFA, provides a highly sensitive (zero false negatives on 50 hERG-sensitive drugs) and highly specific (zero false positives on 50 hERG-insensitive drugs), low-cost hERG safety assay.

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Section: Discussionmentioning

confidence: 99%

Novel cell-free high-throughput screening method for pharmacological tools targeting K ⁺ channels

Brown

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A homozygous mutation in the KCNK3 gene has also been reported in a patient with a severe and early form of PAH who did not carry any other mutations known to be associated with PAH [60]. Potassium channels can modulate vascular tone through regulation of the resting membrane potential in a number of cell types, including SMCs [61,62], and may also play a role in the regulation of cell proliferation and migration [63].…”

Section: Resting Membrane Potentialmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Hemnes

Humbert

2017

Eur Respir Rev

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The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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“…Although the present findings are not adequate to answer these questions, in those tissues where we have directly recorded BK currents or tested for coassembly between LRRC26 and BK α-subunits, LRRC26 appears to be a critical regulatory component of BK channels. Given that a large number of ion channels have been implicated in tumor growth regulation, including KCa3.1 (47,48), calcium channels (49), sodium channels (50), and a variety of K + channels (51,52), these associations raise the possibility that specific ion channels per se may not be intrinsically related to tumor growth regulation, but that some aspect of membrane potential regulation, perhaps linked to cell cycle regulation, is the determinant of whether a given ion channel may promote or impede tumor growth.…”

Section: Potential Roles Of Lrrc26-containing Bk Channels In Tumor Grmentioning

confidence: 99%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca 2+ -and voltage-dependent BK-type K + channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca 2+ , suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K + ] in saliva. LRRC26-containing BK channels are competent to contribute to resting K + efflux at normal cell membrane potentials with resting cytosolic Ca 2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.L arge-conductance, voltage-and Ca 2+ -regulated BK-type channels are widely expressed proteins, found not only in excitable cells, such as neurons, muscle, and endocrine cells, but also nonexcitable cells, including salivary (1) and lacrimal gland (2) acinar cells, and colonic crypt cells (3). Given the almost ubiquitous expression of BK channels among cells that play quite distinct physiological roles, it is particularly important to define the specific properties of BK channels in a given cell type and determine what the specific physiological role played by BK channels in a given cell may be. A hallmark of BK channels is their dual regulation by both membrane voltage and cytosolic Ca 2+ (4), both properties embedded within the tetramer of pore-forming α-subunits of each BK channel (5). However, the specific range of voltages over which a BK channel is active at a given Ca 2+ concentration is markedly dependent on the identity of regulatory subunits that can coassemble with the α-subunit in the mature channel complex. Of the two families of known BK regulatory subunits, β (6-11) and γ (12-14), an important feature of many of these subunits is the ability to shift the range of activation voltages at a given Ca 2+ . Although there is growing information about the loci of expression and functional roles of BK channels containing specific β-subunits (15), much less is known about those BK channels containing the γ1 (LRRC26, leucine-rich-repeat-containing subunit 26) subunit. However, LRRC26 is particularly fascinating because it causes the largest shift in BK gating (approximately −120 mV) of any known non-pore-forming regulatory subunit, resulting in BK channels that...

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Targeting potassium channels in cancer

Cited by 12 publications

References 83 publications

Novel cell-free high-throughput screening method for pharmacological tools targeting K ⁺ channels

Novel cell-free high-throughput screening method for pharmacological tools targeting K ⁺ channels

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

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Targeting potassium channels in cancer

Cited by 12 publications

References 83 publications

Novel cell-free high-throughput screening method for pharmacological tools targeting K + channels

Novel cell-free high-throughput screening method for pharmacological tools targeting K + channels

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

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Product

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Novel cell-free high-throughput screening method for pharmacological tools targeting K ⁺ channels

Novel cell-free high-throughput screening method for pharmacological tools targeting K ⁺ channels