Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia

Schiffhauer, Eric S.; Vij, Neeraj; Kovbasnjuk, Olga; Kang, Po Wei; Walker, Doug; Lee, Seakwoo; Zeitlin, Pamela L.

doi:10.1152/ajplung.00277.2012

Cited by 25 publications

(22 citation statements)

References 40 publications

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“…In addition, GaTx2, shown to differentially inhibit ClC-2, and not CFTR, Cl Ϫ currents (47) also prove to be very useful in resolving these two channels in complex epithelia such as T84 cells. It must be noted that whichever inhibitor (CFTR inh 172, methadone, DASU-02, or GaTx2) is used, there is only partial inhibition (50 -70%) of ClC-2 or CFTR Cl Ϫ currents in all cells or tissues (2,4,7,31,37,47,50).…”

Section: Discussionmentioning

confidence: 99%

Differentiation between human ClC-2 and CFTR Cl⁻ channels with pharmacological agents

Cuppoletti

Chakrabarti

Tewari

et al. 2014

American Journal of Physiology-Cell Physiology

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It has been difficult to separate/identify the roles of ClC-2 and CFTR in Cl(-) transport studies. Using pharmacological agents, we aimed to differentiate functionally between ClC-2 and CFTR Cl(-) channel currents. Effects of CFTR inhibitor 172 (CFTRinh172), N-(4-methylphenylsulfonyl)-N'-(4-trifluoromethylphenyl)urea (DASU-02), and methadone were examined by whole cell patch clamp on Cl(-) currents in recombinant human ClC-2/human embryonic kidney 293 (ClC-2/HEK293) cells stably transformed with Epstein-Barr nuclear antigen 1 (hClC-2/293EBNA) and human CFTR/HEK293 (hCFTR/HEK293) cells and by short-circuit current (Isc) measurements in T84 cells. Lubiprostone and forskolin-IBMX were used as activators. CFTRinh172 inhibited forskolin-IBMX-stimulated recombinant human CFTR (hCFTR) and lubiprostone-stimulated recombinant human ClC-2 (hClC-2) Cl(-) currents in a concentration-dependent manner equipotently. DASU-02 inhibited forskolin-IBMX-stimulated Cl(-) currents in hCFTR/HEK293 cells, but not lubiprostone-stimulated Cl(-) currents in hClC-2/293EBNA cells. In T84 cells with basolateral nystatin or 1-ethyl-2-benzimidazolinone (1-EBIO), lubiprostone-stimulated and forskolin-IBMX-cyclosporin A (FICA)-stimulated Isc components were observed. CFTRinh172 inhibited major portions of both components. DASU-02 had no effect on lubiprostone-stimulated Isc but partially inhibited FICA-stimulated Isc. T84 cells in which ClC-2 or CFTR was knocked down using siRNAs were constructed. T84 ClC-2 knockdown cells did not respond to lubiprostone but did respond to forskolin-IBMX in a methadone-insensitive, DASU-02-sensitive manner, indicating CFTR function. T84 CFTR knockdown cells responded separately to lubiprostone and forskolin-IBMX in a methadone-sensitive and DASU-02-insensitive manner, indicating ClC-2 function. Low lubiprostone concentrations activated ClC-2, but not CFTR, and both channels were activated by forskolin-IBMX but have different inhibitor sensitivities. Methadone, but not DASU-02, inhibited ClC-2. DASU-02, but not methadone, inhibited CFTR. In T84 cells, both ClC-2 and CFTR are present and likely play roles in Cl(-) secretion.

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Section: Discussionmentioning

confidence: 99%

Differentiation between human ClC-2 and CFTR Cl⁻ channels with pharmacological agents

Cuppoletti

Chakrabarti

Tewari

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Drugs approved for OIC (Table 1) Lubiprostone Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 (PGE1) metabolite which increases fluid secretion in the gastrointestinal tract [Cuppoletti et al 2004[Cuppoletti et al , 2014 by stimulating the cystic fibrosis transmembrane regulator and type 2 chloride channels (ClC2) in the apical membrane to secrete chloride and water into the lumen [Bijvelds et al 2009;Schiffhauer et al 2013]. This results in increased peristalsis, laxation, and acceleration of small intestinal and colonic transit [Camilleri et al 2006].…”

Section: Barriers To Diagnosis Of Oicmentioning

confidence: 99%

Opioid-induced constipation: advances and clinical guidance

Nelson

Camilleri

2016

Therapeutic Advances in Chronic Disease

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Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain.

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“…However, there are several alternate mechanisms of action of lubiprostone revealed by recent studies including ion transporter trafficking, mucus release, and smooth muscle contraction. 9,11,98,102,106,[110][111][112][113]116,117,[119][120][121][122][123][124][125][126][127][128][129][130][131] Cobiprostone, another synthetic member of the prostone family, also serves as a ClC-2 agonist and is an investigational prostone as a potential treatment for gastrointestinal, liver and respiratory diseases. In previous research, cobiprostone dosedependently activated ClC-2 in a protein kinase A-independent manner in vitro and protected against formation of gastric ulcers induced by NSAIDs and stress in in vivo.…”

Section: Pharmaceutical Targeting Of Clc-2mentioning

confidence: 99%

ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target

Jin

Blikslager

2015

Tissue Barriers

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Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia

Cited by 25 publications

References 40 publications

Differentiation between human ClC-2 and CFTR Cl⁻ channels with pharmacological agents

Differentiation between human ClC-2 and CFTR Cl⁻ channels with pharmacological agents

Opioid-induced constipation: advances and clinical guidance

ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target

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Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia

Cited by 25 publications

References 40 publications

Differentiation between human ClC-2 and CFTR Cl− channels with pharmacological agents

Differentiation between human ClC-2 and CFTR Cl− channels with pharmacological agents

Opioid-induced constipation: advances and clinical guidance

ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target

Contact Info

Product

Resources

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Differentiation between human ClC-2 and CFTR Cl⁻ channels with pharmacological agents

Differentiation between human ClC-2 and CFTR Cl⁻ channels with pharmacological agents