| Title | Alpha2-adrenergic receptors attenuate secretagogue-induced endocytosis and promote exocytosis of intestinal NHE2 and NHE3. | | Author(s) | Musch MW, Arvans DL, Paris H, Chang E | | Institution | U Chicago. | | Source | J Pharmacol Exp Ther 2009 Jun 25. | | Abstract | Adrenergic agonists, through activation of intestinal epithelial alpha 2-adrenergic receptors (a2AR), inhibit electrolyte secretion and promote absorption. The mechanisms of action to promote basal Na(+) absorption and inhibit stimulated secretion are incompletely understood. The effects of alpha 2-agonists on Na(+) transport were studied in a cell line, Caco2-3B, derived from the Caco2 cell line engineered to permanently express human alpha2A-adrenergic receptors. Serosal, but not mucosal, addition of the a2AR agonist clonidine increased Caco2-3B apical (22)Na(+) uptake, an effect not seen in the Caco2 parent line that lacks a2AR expression. This effect was blocked by the a2AR antagonist yohimbine. Increased Na(+) uptake was paralleled by increased apical surface abundance of the sodium/hydrogen exchangers NHE2 and NHE3. No changes in total cell NHE2 and NHE3 expression were observed. Clonidine also inhibited both cAMP and Ca(++)-induced decreases in apical Na(+) uptake and apical membrane NHE2 and NHE3 endocytosis stimulated by these agents. A2AR actions were mediated via stimulation of phospholipase C and metabolism of arachidonic acid by an epoxygenase activity followed epidermal growth factor release and activation of the EGF receptor, resulting in phosphatidyl inositol-3-kinase and Akt stimulation. In summary, activation of intestinal epithelial a2AR significantly blocks the inhibition of apical Na(+) transporters by cAMP- and Ca(++)-mediated pathways and also directly increases apical sodium/hydrogen exchange activities. By both blocking electrolyte secretion and promoting absorption, alpha2-agonists could be potent anti-diarrheal agents that could directly counteract the actions of toxigenic pathogens and other secretatogues causing secretory diarrhea. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19556451 |
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