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Author Notes:

Address correspondence to: H. Criss Hartzell, Department of Cell Biology, Emory University School of Medicine, 615 Michael St., 535 Whitehead Building, Atlanta, Georgia 30322, USA. Phone: 404.242.5719; Fax: 404.727.6256; E-mail: Criss.Hartzell@emory.edu.

The authors thank Didier Merlin for the use of his Ussing Chamber setup and helpful discussion, Asma Nusrat for advice on histological and pathological analysis, Qinghuan Xiao for comments on the manuscript, Anna Menini for Best2 antibody, the Cystic Fibrosis Foundation for CFTR (3G11) antibody, Nadia Nameen for CFTR antibody, and Uhtaek Oh for Ano1 cDNA.

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

The authors’ work is supported by NIH grants GM60448 (to H.C. Hartzell), EY014852 (to H.C. Hartzell), and EY13160 (to A. Marmorstein); by an American Health Assistance Foundation grant (to A. Marmorstein); by an unrestricted grant to the Department of Ophthalmology and Vision Science at the University of Arizona (to A. Marmorstein); and by Emory University Core Grant for Vision Research P30 EY006360 (to H.C. Hartzell).

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

Tools:

Journal Title:

Journal of Clinical Investigation

Volume:

Volume 120, Number 5

Publisher:

, Pages 1722-1735

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2010, American Society for Clinical Investigation

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