Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

Preston, Patricia M.; Wartosch, Lena; Günzel, Dorothee; Fromm, Michael; Kongsuphol, Patthara; Ousingsawat, Jiraporn; Kunzelmann, Karl; Barhanin, Jacques; Warth, Richard; Jentsch, Thomas J.

doi:10.1074/jbc.m109.047829

Cited by 95 publications

(126 citation statements)

References 70 publications

(61 reference statements)

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“…In intestine (Fig. 1G-L), consistent with previous work, 21,22 KCNQ1 immunoreactivity was observed in basolateral membranes of crypt epithelial cells. Although we did not find colocalization of KCNQ1 and GLP-1 in intestinal villi, KCNQ1 was detected in the GLP-1 positive cell in intestinal crypt.…”

Section: Resultssupporting

confidence: 80%

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Liu

Wang

et al. 2014

Islets

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Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic b-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive b-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

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Section: Resultssupporting

confidence: 80%

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Liu

Wang

et al. 2014

Islets

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“…The LCA results were surprising, since we saw no evidence of a change in net I sc and suggested that LCA was simultaneously activating an opposing current that nullified these changes in AM I sc . A likely mechanism would be an inhibition of basolateral cation conductances, and it is well established that the secretagogue action of cAMP and Ca 2ϩ involves the activation of distinct K ϩ channels (59,74). In T84 cells, Devor (20,22,33), Tabcharani (70,71), and Sheikh (68) demonstrated that the K ϩ channels involved in cAMP-and Ca 2ϩ -mediated secretion are different; cAMP action involves the KCNE3/ KCNQ1 channel, and Ca 2ϩ activates the KCNN4 and KC-NMA1 (MaxiK) channels.…”

Section: Discussionmentioning

confidence: 99%

Lithocholic acid attenuates cAMP-dependent Cl⁻ secretion in human colonic epithelial T84 cells

Mei

Domingue

Khan

et al. 2016

American Journal of Physiology-Cell Physiology

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Bile acids (BAs) play a complex role in colonic fluid secretion. We showed that dihydroxy BAs, but not the monohydroxy BA lithocholic acid (LCA), stimulate Cl Ϫ secretion in human colonic T84 cells (Ao M, Sarathy J, Domingue J, Alrefai WA, Rao MC. Am J Physiol Cell Physiol 305: C447-C456, 2013). In this study, we explored the effect of LCA on the action of other secretagogues in T84 cells. While LCA (50 M, 15 min) drastically (Ͼ90%) inhibited FSK-stimulated short-circuit current (Isc), it did not alter carbachol-stimulated Isc. LCA did not alter basal Isc, transepithelial resistance, cell viability, or cytotoxicity. LCA's inhibitory effect was dose dependent, acted faster from the apical membrane, rapid, and not immediately reversible. LCA also prevented the I sc stimulated by the cAMP-dependent secretagogues 8-bromocAMP, lubiprostone, or chenodeoxycholic acid (CDCA). The LCA inhibitory effect was BA specific, since CDCA, cholic acid, or taurodeoxycholic acid did not alter FSK or carbachol action. While LCA alone had no effect on intracellular cAMP concentration ([cAMP] i), it decreased FSK-stimulated [cAMP]i by 90%. Although LCA caused a small increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i), chelation by BAPTA-AM did not reverse LCA's effect on I sc. LCA action does not appear to involve known BA receptors, farnesoid X receptor, vitamin D receptor, muscarinic acetylcholine receptor M3, or bile acid-specific transmembrane G protein-coupled receptor 5. LCA significantly increased ERK1/2 phosphorylation, which was completely abolished by the MEK inhibitor PD-98059. Surprisingly PD-98059 did not reverse LCA's effect on I sc. Finally, although LCA had no effect on basal I sc, nystatin permeabilization studies showed that LCA both stimulates an apical cystic fibrosis transmembrane conductance regulator Cl Ϫ current and inhibits a basolateral K ϩ current. In summary, 50 M LCA greatly inhibits cAMP-stimulated Cl Ϫ secretion, making low doses of LCA of potential therapeutic interest for diarrheal diseases.

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“…The short form of KCNE3 protein that is expressed in mice migrates much more slowly (;37 kDa) in SDS-PAGE than would be predicted solely from its 103-residue length (;14 kDa), primarily because of glycosylation (3 sites) (5,14,38). Deglycosylation eliminates the 37-kDa band and leaves a single band for mouse KCNE3 at 14 kDa (38). The newly discovered portion of hKCNE3 does not contain additional consensus glycosylation sites (Fig.…”

Section: Experimental Validation Of Extended Hkcne3 and Hkcne4 Proteimentioning

confidence: 99%

Novel exon 1 protein‐coding regions N‐terminally extend human KCNE3 and KCNE4

Abbott

2016

FASEB j.

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The 5 human (h)KCNE b subunits each regulate various cation channels and are linked to inherited cardiac arrhythmias. Reported here are previously undiscovered protein-coding regions in exon 1 of hKCNE3 and hKCNE4 that extend their encoded extracellular domains by 44 and 51 residues, which yields full-length proteins of 147 and 221 residues, respectively. Full-length hKCNE3 and hKCNE4 transcript and protein are expressed in multiple human tissues; for hKCNE4, only the longer protein isoform is detectable. Twoelectrode voltage-clamp electrophysiology revealed that, when coexpressed in Xenopus laevis oocytes with various potassium channels, the newly discovered segment preserved conversion of KCNQ1 by hKCNE3 to a constitutively open channel, but prevented its inhibition of Kv4.2 and KCNQ4. hKCNE4 slowing of Kv4.2 inactivation and positive-shifted steady-state inactivation were also preserved in the longer form. In contrast, full-length hKCNE4 inhibition of KCNQ1 was limited to 40% at +40 mV vs. 80% inhibition by the shorter form, and augmentation of KCNQ4 activity by hKCNE4 was entirely abolished by the additional segment. Among the genome databases analyzed, the longer KCNE3 is confined to primates; full-length KCNE4 is widespread in vertebrates but is notably absent from Mus musculus. Findings highlight unexpected KCNE gene diversity, raise the possibility of dynamic regulation of KCNE partner modulation via splice variation, and suggest that the longer hKCNE3 and hKCNE4 proteins should be adopted in future mechanistic and genetic screening studies.-Abbott, G. W. Novel exon 1 protein-coding regions N-terminally extend human KCNE3 and KCNE4. FASEB J. 30, 2959-2969(2016. www.fasebj.orgIon channels are complex macromolecules that consist of multiple pore-forming and non-pore-forming subunits in vivo. Voltage-gated potassium (Kv) channels are a numerous and diverse class generated by 40 different a subunits in human tissues that can each come together to form the functional assembly, a tetramer of a subunits. The 40 a subunits are categorized into several subfamilies, and subfamily-specific heterotetramerization commonly occurs, which further diversifies the resultant complexes and the currents they generate (1). In addition, multiple different classes of non-pore-forming (b) subunits, either transmembrane or cytosolic, can coassemble with Kv a subunits to create the considerable complexity required for normal cellular functions of higher animals (2).The most widely studied group of transmembrane Kv b subunits are the KCNE proteins, also referred to as MinK-related peptides (3, 4), with .1000 published studies on this gene family to date. KCNE proteins are so widely studied because they can exert sometimes dramatic effects on Kv channel function (5-11), are obligate partners for many Kv a subunits in vivo (5, 6, 9-17), can alter Kv channel pharmacology with respect to clinically relevant and investigational drugs (18,19), and their reach is impressive, each modulating multiple Kv a subunits and, in some c...

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Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

Abstract: The KCNE3 ␤-subunit constitutively opens outwardly rectifying KCNQ1 (Kv7.

Cited by 95 publications

References 70 publications

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Lithocholic acid attenuates cAMP-dependent Cl⁻ secretion in human colonic epithelial T84 cells

Novel exon 1 protein‐coding regions N‐terminally extend human KCNE3 and KCNE4

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Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

Abstract: The KCNE3 ␤-subunit constitutively opens outwardly rectifying KCNQ1 (Kv7.

Cited by 95 publications

References 70 publications

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Lithocholic acid attenuates cAMP-dependent Cl− secretion in human colonic epithelial T84 cells

Novel exon 1 protein‐coding regions N‐terminally extend human KCNE3 and KCNE4

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Lithocholic acid attenuates cAMP-dependent Cl⁻ secretion in human colonic epithelial T84 cells