α2-Adrenergic Receptors Attenuate Secretagogue-Induced Endocytosis and Promote Exocytosis of Intestinal NHE2 and NHE3 | Journal of Pharmacology and Experimental Therapeutics
Adrenergic agonists, through activation of intestinal epithelial α2-adrenergic receptors (α2AR), inhibit electrolyte secretion and promote absorption. The mechanisms of action to promote basal Na+ absorption and inhibit stimulated secretion are not understood completely. The effects of α2-agonists on Na+ transport were studied in a cell line, Caco2-3B, derived from the Caco2 cell line engineered to permanently express human α2A-adrenergic receptors. Serosal, but not mucosal, addition of the α2AR agonist N -(2,6-dichlorophenyl)-4,5-dihydro-1 H -imidazol-2-amine (clonidine) increased Caco2-3B apical 22Na+ uptake, an effect not seen in the Caco2 parent line that lacks α2AR expression. This effect was blocked by the α2AR antagonist 17α-yohmban-16α-carboxylic acid methyl ester (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 Ca2+-induced decreases in apical Na+ uptake and apical membrane NHE2 and NHE3 endocytosis stimulated by these agents. α2AR 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 epidermal growth factor receptor, resulting in phosphatidylinositol-3-kinase and Akt stimulation. In summary, activation of intestinal epithelial α2AR significantly blocks the inhibition of apical Na+ transporters by cAMP- and Ca2+-mediated pathways and also directly increases apical sodium/hydrogen exchange activities. By both blocking electrolyte secretion and promoting absorption, α2-agonists could be potent antidiarrheal agents that could directly counteract the actions of toxigenic pathogens and other secretagogues causing secretory diarrhea.
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