Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea

Aoun, Joydeep; Hayashi, Mikio; Sheikh, Irshad Ali; Sarkar, Paramita; Saha, Tultul; Ghosh, Priyanka; Bhowmick, Rajsekhar; Ghosh, Dipanjan; Chatterjee, Tanaya; Chakrabarti, Pinak; Chakrabarti, Manoj K.; Hoque, Kazi Mirajul

doi:10.1074/jbc.m116.719823

Cited by 25 publications

(11 citation statements)

References 50 publications

(57 reference statements)

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“…Recent evidence shows that TMEM16 proteins are also regulated by PI(4,5)P2. For example, the TMEM16F phospholipid scramblase is regulated by PI(4,5)P2 in intestinal epithelia stimulated with the accessory cholera enterotoxin (Aoun et al, 2016). This might be because TMEM16F and also TMEM16C, -D, -G, and -J are phospholipid scramblases that transport membrane phospholipids between leaflets of the membrane bilayer (Suzuki et al, 2010; Suzuki et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Jesús-Pérez

Cruz-Rangel

Espino-Saldaña

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The TMEM16A-mediated Ca-activated Cl current drives several important physiological functions. Membrane lipids regulate ion channels and transporters but their influence on members of the TMEM16 family is poorly understood. Here we have studied the regulation of TMEM16A by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), cholesterol, and fatty acids using patch clamp, biochemistry and fluorescence microscopy. We found that depletion of membrane PI(4,5)P2 causes a decline in TMEM16A current that is independent of cytoskeleton, but is partially prevented by removing intracellular Ca. On the other hand, supplying PI(4,5)P2 to inside-out patches attenuated channel rundown and/or partially rescued activity after channel rundown. Also, depletion (with methyl-β-cyclodextrin M-βCD) or restoration (with M-βCD+cholesterol) of membrane cholesterol slows down the current decay observed after reduction of PI(4,5)P2. Neither depletion nor restoration of cholesterol change PI(4,5)P2 content. However, M-βCD alone transiently increases TMEM16A activity and dampens rundown whereas M-βCD+cholesterol increases channel rundown. Thus, PI(4,5)P2 is required for TMEM16A function while cholesterol directly and indirectly via a PI(4,5)P2-independent mechanism regulate channel function. Stearic, arachidonic, oleic, docosahexaenoic, and eicosapentaenoic fatty acids as well as methyl stearate inhibit TMEM16A in a dose- and voltage-dependent manner. Phosphatidylserine, a phospholipid whose hydrocarbon tails contain stearic and oleic acids also inhibits TMEM16A. Finally, we show that TMEM16A remains in the plasma membrane after treatment with M-βCD, M-βCD+cholesterol, oleic, or docosahexaenoic acids. Thus, we propose that lipids and fatty acids regulate TMEM16A channels through a membrane-delimited protein-lipid interaction.

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Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Jesús-Pérez

Cruz-Rangel

Espino-Saldaña

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Cl − secretion to induce diarrhea (Aoun et al, 2016). ANO6 and PIP 2 act as additional mechanisms of secretory diarrhea.…”

Section: Accessory Cholera Enterotoxin (Ace) and Zonula Occludens Toxmentioning

confidence: 99%

“…The role of ANOs in diarrhea is well-investigated in NSP-4 of rotavirus. It was found that phosphatidylinositol 4,5-bisphosphate (PIP 2 ) influences the ANO6 function by Ace stimulation in intestinal epithelium for Cl − secretion to induce diarrhea (Aoun et al, 2016 ). ANO6 and PIP 2 act as additional mechanisms of secretory diarrhea.…”

Section: Major Toxins Produced By V Cholerae and mentioning

confidence: 99%

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae

Ramamurthy

Nandy

Mukhopadhyay

et al. 2020

Front. Cell. Infect. Microbiol.

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The human pathogen Vibrio cholerae is the causative agent of severe diarrheal disease known as cholera. Of the more than 200 "O" serogroups of this pathogen, O1 and O139 cause cholera outbreaks and epidemics. The rest of the serogroups, collectively known as non-O1/non-O139 cause sporadic moderate or mild diarrhea and also systemic infections. Pathogenic V. cholerae circulates between nutrient-rich human gut and nutrient-deprived aquatic environment. As an autochthonous bacterium in the environment and as a human pathogen, V. cholerae maintains its survival and proliferation in these two niches. Growth in the gastrointestinal tract involves expression of several genes that provide bacterial resistance against host factors. An intricate regulatory program involving extracellular signaling inputs is also controlling this function. On the other hand, the ability to store carbon as glycogen facilitates bacterial fitness in the aquatic environment. To initiate the infection, V. cholerae must colonize the small intestine after successfully passing through the acid barrier in the stomach and survive in the presence of bile and antimicrobial peptides in the intestinal lumen and mucus, respectively. In V. cholerae, virulence is a multilocus phenomenon with a large functionally associated network. More than 200 proteins have been identified that are functionally linked to the virulence-associated genes of the pathogen. Several of these genes have a role to play in virulence and/or in functions that have importance in the human host or the environment. A total of 524 genes are differentially expressed in classical and El Tor strains, the two biotypes of V. cholerae serogroup O1. Within the host, many immune and biological factors are able to induce genes that are responsible for survival, colonization, and virulence. The innate host immune response to V. cholerae infection includes activation of several immune protein complexes, receptor-mediated signaling pathways, and other bactericidal proteins. This article presents an overview of regulation of important virulence factors in V. cholerae and host response in the context of pathogenesis.

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“…Inhibiting intestinal sodium absorption through inhibitors of the Na + transporter NHE3, such as SAR218034, results in an increase in fecal sodium excretion and reduction in systolic blood pressure in spontaneously hypertensive rats [14]. In addition to the sodium channels, there are several types of chlorine channels present in enterocytes, such as Ca 2+ -activated Cl - channel (CaCC) and cystic fibrosis transmembrane conductance regulator (CFTR), which are expressed on the apical or luminal membrane to mediate Cl - secretion [15-17]. It’s reported dietary genistein could regulate basal diabetic jejunum Cl - secretion in ob/ob female mice by reduce CFTR expression [18].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats

Wei

Yang

et al. 2018

Kidney Blood Press Res

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Background/Aims: High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. Methods: Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. Results: Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR), and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. Conclusion: The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats.

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Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea

Cited by 25 publications

References 50 publications

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Virulence Regulation and Innate Host Response in the Pathogenicity of Vibrio cholerae

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats

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