TY - JOUR
T1 - Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon
AU - Yu, Kuai
AU - Lujan, Rafael
AU - Marmorstein, Alan
AU - Gabriel, Sherif
AU - Hartzell, H. Criss
PY - 2010/5/3
Y1 - 2010/5/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI41129
DO - 10.1172/JCI41129
M3 - Article
C2 - 20407206
AN - SCOPUS:77951807825
SN - 0021-9738
VL - 120
SP - 1722
EP - 1735
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -