Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon.
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.
Yu
Kuai
K
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Lujan
Rafael
R
Marmorstein
Alan
A
Gabriel
Sherif
S
Hartzell
H Criss
HC
D000818:Animals; D000075002:Bestrophins; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000502:physiology*; D003106:Colon / Q000378:metabolism*; D005136:Eye Proteins / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype
C497463:Best2 protein, mouse; D000075002:Bestrophins; D001639:Bicarbonates; D018118:Chloride Channels; D005136:Eye Proteins; D002118:Calcium
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