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

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

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 Ca 2+-activated Cl- channels (CaCCs) or an increase in the Cl- driving force through CFTR after activation of Ca 2+-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 HCO 3-, 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.

Original languageEnglish (US)
Pages (from-to)1722-1735
Number of pages14
JournalJournal of Clinical Investigation
Volume120
Issue number5
DOIs
StatePublished - May 3 2010
Externally publishedYes

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Goblet Cells
Bicarbonates
Cholinergic Agents
Anions
Colon
Membranes
Chloride-Bicarbonate Antiporters
Transcytosis
Cholinergic Agonists
Enterocytes
Mucins
Mucous Membrane
Homeostasis
Down-Regulation
Proteins

ASJC Scopus subject areas

  • Medicine(all)

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Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon. / Yu, Kuai; Lujan, Rafael; Marmorstein, Alan D; Gabriel, Sherif; Hartzell, H. Criss.

In: Journal of Clinical Investigation, Vol. 120, No. 5, 03.05.2010, p. 1722-1735.

Research output: Contribution to journalArticle

Yu, Kuai ; Lujan, Rafael ; Marmorstein, Alan D ; Gabriel, Sherif ; Hartzell, H. Criss. / Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 5. pp. 1722-1735.
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