The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators

Almássy, János; Begenisich, Ted

doi:10.1124/mol.111.075234

Cited by 38 publications

(63 citation statements)

References 35 publications

(21 reference statements)

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“…BK KO results in decreased K + concentrations in secreted fluid from mouse submandibular (31) and parotid (1) glands. The results here confirm that, in parotid, submandibular, and lacrimal gland, the shifted gating of BK channels in those cells arises from the presence of LRRC26, as originally suggested by Begenisich and colleagues in regards to parotid (18,19). Here we tested the possibility that the simple absence of the LRRC26 subunit might be sufficient to mimic the effects of BK α-subunit KO.…”

Section: Discussionsupporting

confidence: 71%

“…There is also some pharmacological and functional evidence supporting the presence of LRRC26-containing BK channels in tracheal epithelium (37), based on the presence of a mallotoxin-resistant component of a BK-dependent process. Mallotoxin has been shown to be an activator of BK channels at low nanomolar concentrations (38), but heterologously expressed BK channels containing LRRC26 are resistant to mallotoxin as are the native BK channels in parotid (19). The specific identity of the tracheal cell type that participates in that phenomenon has not been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Previous functional data have suggested the presence of LRRC26-containing BK channels in prostate tumor cells (12,17) and parotid acinar cells (18,19). Other tissues in which BK channels appear to be activated at unusually negative voltage ranges include lacrimal gland (2,35) and pancreatic acinar cells (36).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently it was shown to be a regulatory subunit of BK channels (12), later defined as γ1 (14). LRRC26 accounts for the large shift in BK activation toward negative potentials found in LNCaP prostate tumor cells (17), whereas similar shifts in BK gating attributable to LRRC26 have also been observed in mouse parotid gland acinar cells (18,19). In other cases where the presence of LRRC26 has been suggested, definitive evidence of BK channels with properties consistent with the presence of LRRC26 is lacking.…”

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confidence: 96%

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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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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

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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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“…To evaluate whether these changes translated to altered functional activity, the BK opener mallotoxin (MTX (5 M)) was used. MTX potently shifts the conductance-voltage relationship of BK channels to the left (25), but only in the absence of LRRC26. Control CFBE cells did not respond to MTX, whereas TGF-␤1-treated cells showed increased apical K ϩ secretion upon MTX exposure (Fig.…”

Section: Journal Of Biological Chemistry 25711mentioning

confidence: 99%

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

Manzanares

Krick

Baumlin

et al. 2015

Journal of Biological Chemistry

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Background: TGF-␤ is associated with worse outcome in cystic fibrosis (CF). Results: TGF-␤ causes mucociliary dysfunction by reducing airway surface liquid (ASL) due to decreased apical BK channel activity and down-regulation of its ␥ subunit LRRC26. Conclusion:The TGF-␤ inhibitor pirfenidone reverses ASL loss via BK and LRRC26 rescue. Significance: Clinical trials could test the usefulness of pirfenidone in CF.

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Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

269

347

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators

Cited by 38 publications

References 35 publications

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

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

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

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