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AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon.

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.

Authors+Show Affiliations

Department of Physiology, University of Utah, Salt Lake City, Utah 84108, USA. Lara.Gawenis@hsc.utah.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20110461

Citation

Gawenis, Lara R., et al. "AE2 Cl-/HCO3- Exchanger Is Required for Normal cAMP-stimulated Anion Secretion in Murine Proximal Colon." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 298, no. 4, 2010, pp. G493-503.
Gawenis LR, Bradford EM, Alper SL, et al. AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon. Am J Physiol Gastrointest Liver Physiol. 2010;298(4):G493-503.
Gawenis, L. R., Bradford, E. M., Alper, S. L., Prasad, V., & Shull, G. E. (2010). AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon. American Journal of Physiology. Gastrointestinal and Liver Physiology, 298(4), pp. G493-503. doi:10.1152/ajpgi.00178.2009.
Gawenis LR, et al. AE2 Cl-/HCO3- Exchanger Is Required for Normal cAMP-stimulated Anion Secretion in Murine Proximal Colon. Am J Physiol Gastrointest Liver Physiol. 2010;298(4):G493-503. PubMed PMID: 20110461.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon. AU - Gawenis,Lara R, AU - Bradford,Emily M, AU - Alper,Seth L, AU - Prasad,Vikram, AU - Shull,Gary E, Y1 - 2010/01/28/ PY - 2010/1/30/entrez PY - 2010/1/30/pubmed PY - 2010/4/17/medline SP - G493 EP - 503 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 298 IS - 4 N2 - 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. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/20110461/AE2_Cl_/HCO3__exchanger_is_required_for_normal_cAMP_stimulated_anion_secretion_in_murine_proximal_colon_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00178.2009?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -