Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon
Kuai Yu, … , Sherif Gabriel, H. Criss Hartzell
Kuai Yu, … , Sherif Gabriel, H. Criss Hartzell
Published April 19, 2010
Citation Information: J Clin Invest. 2010;120(5):1722-1735. https://doi.org/10.1172/JCI41129.
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Research Article Gastroenterology

Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

Abstract

Anion transport by the colonic mucosa maintains the hydration and pH of the colonic lumen, and its disruption causes a variety of diarrheal diseases. Cholinergic agonists raise cytosolic Ca2+ levels and stimulate anion secretion, but the mechanisms underlying this effect remain unclear. Cholinergic stimulation of anion secretion may occur via activation of Ca2+-activated Cl– channels (CaCCs) or an increase in the Cl– driving force through CFTR after activation of Ca2+-dependent K+ channels. Here we investigated the role of a candidate CaCC protein, bestrophin-2 (Best2), using Best2–/– mice. Cholinergic stimulation of anion current was greatly reduced in Best2–/– mice, consistent with our proposed role for Best2 as a CaCC. However, immunostaining revealed Best2 localized to the basolateral membrane of mucin-secreting colonic goblet cells, not the apical membrane of Cl–-secreting enterocytes. In addition, in the absence of HCO3–, cholinergic-activated current was identical in control and Best2–/– tissue preparations, which suggests that most of the Best2 current was carried by HCO3–. These data delineate an alternative model of cholinergic regulation of colonic anion secretion in which goblet cells play a critical role in HCO3– homeostasis. We therefore propose that Best2 is a HCO3– channel that works in concert with a Cl:HCO3– exchanger in the apical membrane to affect transcellular HCO3– transport. Furthermore, previous models implicating CFTR in cholinergic Cl– secretion may be explained by substantial downregulation of Best2 in Cftr–/– mice.

Authors

Kuai Yu, Rafael Lujan, Alan Marmorstein, Sherif Gabriel, H. Criss Hartzell

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Figure 10

Ion transport in distal colon.

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Ion transport in distal colon. (A) Transporters and channels in colon. T...
(A) Transporters and channels in colon. The distribution of channels and transporters was determined by immunofluorescence confocal microscopy. Secretion occurs in the crypt, and absorption occurs at the luminal brush border. Secretion is driven by transepithelial Cl– transport that occurs by active basolateral uptake of Cl– by the Na+/K+/2Cl– cotransporter NKCC1 (blue) and subsequent passive efflux via apical CFTR Cl– channels (green). Cl– transport is accompanied — paracellularly and possibly transcellularly — by H2O and and Na+ (gray). Na+ and Cl– are then reabsorbed at the brush border surface by coupled Na+-H+ exchange (by NHE3; orange) and Cl–-HCO3– exchange (by SLC26A3; magenta) coupled to carbonic anhydrase (CA). Best2 (brown) is expressed basolaterally in goblet cells. Na+ is also reabsorbed by the ENaC (not shown). HCO3– is taken up by basolateral NBCe1 (pink), but apical mechanisms are not clear. (B) Interaction of goblet cells and enterocytes. Goblet cells (brown) are hypothesized to secrete HCO3– by transcellular transport involving Best2 in the basolateral membrane and a Cl:HCO3– transporter in the apical membrane (see Discussion). Enterocytes (blue) secrete Cl– by transcellular transport involving basolateral NKCC1 and apical CFTR.