Abstract
Anion secretion by colonic epithelium is dependent on apical CFTR-mediated anion conductance and basolateral ion transport. In many tissues, the NKCC1 Na(+)-K(+)-2Cl(-) cotransporter mediates basolateral Cl(-) uptake. However, additional evidence suggests that the AE2 Cl(-)/HCO(3)(-) exchanger, when coupled with the NHE1 Na(+)/H(+) exchanger or a Na(+)-HCO(3)(-) cotransporter (NBC), contributes to HCO(3)(-) and/or Cl(-) uptake. To analyze the secretory functions of AE2 in proximal colon, short-circuit current (I(sc)) responses to cAMP and inhibitors of basolateral anion transporters were measured in muscle-stripped wild-type (WT) and AE2-null (AE2(-/-)) proximal colon. In physiological Ringer, the magnitude of cAMP-stimulated I(sc) was the same in WT and AE2(-/-) colon. However, the I(sc) response in AE2(-/-) colon exhibited increased sensitivity to the NKCC1 inhibitor bumetanide and decreased sensitivity to the distilbene derivative SITS (which inhibits AE2 and some NBCs), indicating that loss of AE2 results in a switch to increased NKCC1-supported anion secretion. Removal of HCO(3)(-) resulted in robust cAMP-stimulated I(sc) in both AE2(-/-) and WT colon that was largely mediated by NKCC1, whereas removal of Cl(-) resulted in sharply decreased cAMP-stimulated I(sc) in AE2(-/-) colon relative to WT controls. Inhibition of NHE1 had no effect on cAMP-stimulated I(sc) in AE2(-/-) colon but caused a switch to NKCC1-supported secretion in WT colon. Thus, in AE2(-/-) colon, Cl(-) secretion supported by basolateral NKCC1 is enhanced, whereas HCO(3)(-) secretion is diminished. These results show that AE2 is a component of the basolateral ion transport mechanisms that support anion secretion in the proximal colon.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-3-isobutylxanthine / pharmacology
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4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / pharmacology
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Acetazolamide / pharmacology
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Amiloride / analogs & derivatives
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Amiloride / pharmacology
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Animals
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Animals, Newborn
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Anion Transport Proteins / antagonists & inhibitors
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Anion Transport Proteins / genetics
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Anion Transport Proteins / metabolism*
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Anions / metabolism*
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Antiporters / antagonists & inhibitors
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Antiporters / genetics
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Antiporters / metabolism*
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Bicarbonates / metabolism
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Bumetanide / pharmacology
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Carbonic Anhydrase II / genetics
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Carbonic Anhydrase II / metabolism
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Carbonic Anhydrase III / genetics
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Carbonic Anhydrase III / metabolism
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Carbonic Anhydrase Inhibitors / pharmacology
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Carbonic Anhydrases / genetics
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Carbonic Anhydrases / metabolism
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Cation Transport Proteins / antagonists & inhibitors
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Cation Transport Proteins / metabolism
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Cecum / pathology
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Chlorides / metabolism
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Colforsin / pharmacology
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Colon / drug effects
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Colon / metabolism*
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Colon / pathology
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Cyclic AMP / physiology*
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Electrophysiological Phenomena
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Gene Expression / genetics
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Ion Channels / genetics
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Ion Pumps / genetics
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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SLC4A Proteins
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers / antagonists & inhibitors
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Sodium-Hydrogen Exchangers / metabolism
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Sodium-Potassium-Chloride Symporters / drug effects
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Sodium-Potassium-Chloride Symporters / metabolism
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Solute Carrier Family 12, Member 2
Substances
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Anion Transport Proteins
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Anions
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Antiporters
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Bicarbonates
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Carbonic Anhydrase Inhibitors
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Cation Transport Proteins
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Chlorides
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Ion Channels
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Ion Pumps
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SLC4A Proteins
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Slc12a2 protein, mouse
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Slc4a3 protein, mouse
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Slc9a1 protein, mouse
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers
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Sodium-Potassium-Chloride Symporters
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Solute Carrier Family 12, Member 2
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Bumetanide
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Colforsin
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4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid
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Amiloride
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Cyclic AMP
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Carbonic Anhydrase II
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Carbonic Anhydrase III
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Carbonic Anhydrases
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Acetazolamide
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1-Methyl-3-isobutylxanthine
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ethylisopropylamiloride