Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea

Duan, Tianying; Çil, Onur; Thiagarajah, Jay R.

doi:10.1172/jci.insight.126444

Cited by 40 publications

(39 citation statements)

References 61 publications

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“…Forskolin-induced Cl – secretion in intestinal cells involves the coordinated action of several transporters, including apical membrane CFTR, and basolateral membrane K + channels and cotransporters ( 4 ). To ascribe the cinacalcet inhibition of I SC in T84 cells to an action on CFTR, I SC was measured in T84 cells following selective permeabilization of the basolateral membrane in the presence of a basolateral-to-apical Cl – gradient, in which I SC provides a direct measure of apical membrane Cl – conductance ( 19 ). In this setting cinacalcet pretreatment largely inhibited forskolin-induced Cl – secretion and the CFTR inh -172 effect ( Figure 4, C and D ).…”

Section: Resultsmentioning

confidence: 99%

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Oak¹,

Chhetri²,

Rivera³

et al. 2021

JCI Insight

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Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures, such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca 2+ . The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl – secretion by greater than 80%. Cinacalcet also reduced Cl – secretion induced by cholera toxin, heat-stable E . coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator–mediated (CFTR-mediated) Cl – secretion following activation of CaSR and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed loop models of cholera and traveler’s diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3–mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas, including cholera, traveler’s diarrhea, and VIPoma.

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Section: Resultsmentioning

confidence: 99%

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Oak¹,

Chhetri²,

Rivera³

et al. 2021

JCI Insight

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“…Notwithstanding these caveats, we conclude that CFTR is a primary ion channel target in BAD and, hence, its pharmacological inhibition could have therapeutic efficacy in BAD as well as IBS-D. BAD thus adds to the list of potential diarrheal indications of CFTR inhibitor therapy, which include diarrheas caused by bacterial enterotoxins such as cholera and traveler's diarrhea (enterotoxigenic E. coli), certain endocrine gastrointestinal tumors, some congenital diarrheas, and some chemotherapeutic diarrheas (20). Figure 8.…”

Section: Discussionmentioning

confidence: 87%

“…These results implicate CFTR as a major prosecretory ion channel in CDCA-induced diarrhea in human colonic cell cultures and rodents. BPO-27 is a small-molecule CFTR-selective inhibitor with an IC 50 of ;4 nM in cell models that has shown efficacy in rodent model of cholera, traveler's diarrhea, and tyrosine kinase inhibitor-induced diarrhea (18,20). BPO-27 stabilizes the CFTR closed state by patch-clamp analysis and appears at the molecular level to compete with ATP at the canonical ATP binding site in CFTR (36).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we used cell cultures, including human colonic epithelial cultures (colonoids), intestinal fragments, and closed intestinal loops in vivo, to study bile acid-mediated stimulation of ion and fluid transport. Motivated by data from these systems implicating CFTR as a major determinant of bile acid-induced colonic ion and fluid secretion, we established a rat model of BAD to test the efficacy of a small-molecule CFTR inhibitor that has previously shown efficacy in experimental animal models of cholera toxin, heat-stable Escherichia coli enterotoxin, and tyrosine kinase inhibitor-induced diarrheas (18)(19)(20).…”

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confidence: 99%

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Inhibition of CFTR‐mediated intestinal chloride secretion as potential therapy for bile acid diarrhea

et al. 2019

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Bile acid diarrhea (BAD) is common with ileal resection, Crohn's disease, and diarrhea‐predominant irritable bowel syndrome. Here, we demonstrate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (R)‐benzopyrimido‐pyrrolo‐oxazine‐dione‐27 (BPO‐27) in reducing bile acid‐induced fluid and electrolyte secretion in colon. Short‐circuit current measurements in human T84 colonic epithelial cells and planar colonic enteroid cultures showed a robust secretory response following mucosal but not serosal addition of chenodeoxycholic acid (CDCA) or its taurine conjugate, which was fully blocked by CFTR inhibitors, including (R)‐BPO‐27. (R)‐BPO‐27 also fully blocked CDCA‐induced secretory current in murine colon. CFTR activation by CDCA primarily involved Ca2+ signaling. In closed colonic loops in vivo, luminal CDCA produced a robust secretory response, which was reduced by ~70% by (R)‐BPO‐27 or in CFTR‐deficient mice. In a rat model of BAD produced by intracolonic infusion of CDCA, (R)‐BPO‐27 reduced the elevation in stool water content by >55%. These results implicate CFTR activation in the colon as a major prosecretory mechanism of CDCA, a bile acid implicated in BAD, and support the potential therapeutic efficacy of CFTR inhibition in bile acid‐associated diarrheas.—Duan, T., Cil, O., Tse, C. M., Sarker, R., Lin, R., Donowitz, M., Verkman, A. S. Inhibition of CFTR‐mediated intestinal chloride secretion as potential therapy for bile acid diarrhea. FASEB J. 33, 10924–10934 (2019). http://www.fasebj.org

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“…IEC monolayers were preincubated for 24 and 48 hours with IFN-γ. As pharmacological K + channel modulators we used the KCNN4 opener SKA-31 at a concentration of 5 µM [37] as well as the KCNN4 opener 1-EBIO at a concentration of 600 µM [38]. Moreover, we used the following KCNN4 inhibitors: TRAM-34 (25 µM) [39,40] and clotrimazole (10 µM) [39].…”

Section: Permeability Assaymentioning

confidence: 99%

KCNN4 Expression Is Elevated in Inflammatory Bowel Disease: This Might Be a Novel Marker and Therapeutic Option Targeting Potassium Channels

Süß

Broncy

Pollinger

et al. 2020

JGLD

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Background and Aims: The K + channel KCNN4 is involved in many inflammatory diseases. Previous work has shown that this channel is involved in epithelial ion transport and intestinal restitution. In inflammatory bowel diseases (IBD) a defective epithelial barrier can lead to typical symptoms like secretory diarrhea and the formation of intestinal ulcers. We compared surgical samples from patients with IBD, diverticulitis and controls without inflammation to determine the potential role of KCNN4 as a diagnostic marker and/or therapeutic target. Methods: mRNA-levels of KCNN4 and a control K + channel were determined in intestinal epithelial cells (IEC) from patients with IBD, diverticulitis and controls. In addition, we performed a Western blot analysis of KCNN4 and a respective control K + channel in IEC from patients with IBD. Furthermore, we determined epithelial barrier integrity by measuring the flux of fluorescent-labeled dextran beads across a cell monolayer upon incubation with interferon-γ. Results: KCNN4 mRNA and protein levels were elevated in IEC from patients with Crohn`s disease (CD) and ulcerative colitis (UC). Of note, KCNN4 was not elevated in non-IBD intestinal inflammatory conditions e.g. diverticulitis. Of clinical relevance, pharmacological KCNN4 channel openers stabilized epithelial barrier function in vitro. Thus, KCNN4 may have a protective role in IBD and constitute a therapeutic target. Conclusions: Our data demonstrate elevated KCNN4 both at mRNA and protein level in IEC specifically from patients with IBD. Therefore, we conclude that KCNN4 could be used as a novel marker for IBD, especially for the establishment of initial diagnosis. Of therapeutic consequence, we show that pharmacological KCNN4 openers stabilize the epithelial barrier. Thus, KCNN4 might be a novel target to diagnose and treat IBD.

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Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea

Cited by 40 publications

References 61 publications

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Inhibition of CFTR‐mediated intestinal chloride secretion as potential therapy for bile acid diarrhea

KCNN4 Expression Is Elevated in Inflammatory Bowel Disease: This Might Be a Novel Marker and Therapeutic Option Targeting Potassium Channels

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