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Vol. 294, Issue 2, 466-472, August 2000

alpha 2-Adrenergic Receptors Stimulate Oligopeptide Transport in a Human Intestinal Cell Line1

Françoise Berlioz , Jean-José Maoret, Hervé Paris, Marc Laburthe, Robert Farinotti and Claude Rozé

Institut National de la Santé et de la Recherche Médicale, Faculté X. Bichat, Paris (F.B., J.-J.M., M.L., C.R.); Institut National de la Santé et de la Recherche Médicale, Institut Louis Bugnard, Toulouse (H.P.); and Unité Propre de Recherches de I'Enseignement Supérieure, Faculté de Pharmacie, Chatenay-Malabry, France (F.B., R.F.)

Di- and tripeptides, as well as peptidomimetic drugs such as cephalexin (CFX), are absorbed by enterocytes via the oligopeptide transporter PepT1. We recently showed that the alpha 2-adrenergic agonist clonidine increases CFX absorption in anaesthetized rats. Herein, we investigated whether alpha 2-adrenergic receptors can directly affect PepT1 activity in a clone of the differentiated human intestinal cell line Caco-2 (Caco-2 3B) engineered to stably express alpha 2A-adrenergic receptors at a density similar to that found in normal mucosa. Measurement of CFX fluxes across cell monolayers cultured on transwell filters demonstrated that the alpha 2-agonists clonidine and UK14304 caused a 2-fold increase of CFX transport in Caco-2 3B cells, but not in Caco-2 (expressing PepT1 but not alpha 2-adrenergic receptors) or in the HT29 19A clone (expressing alpha 2-adrenergic receptors but not PepT1). The stimulatory effect of clonidine was abolished by glycyl-sarcosine (a competitor for the transporter) and blocked by yohimbine or RX821002 (alpha 2-antagonists). Analysis of the kinetics of CFX transport in control and clonidine-treated Caco-2 3B cells showed that clonidine increased Vmax of CFX transport without changing Km. Clonidine action was abolished by colchicine but not altered by amiloride, demonstrating that microtubule integrity but not Na+/H+ exchanger activity is necessary for the effect of alpha 2-agonists to occur. In conclusion, clonidine can directly activate alpha 2-adrenergic receptors located on epithelial cells. The precise molecular mechanisms whereby these receptors modulate PepT1 activity remain to be elucidated but an increased translocation to the apical membrane of preformed cytoplasmic transporter molecules is likely to be involved.

1 This study was funded in part by Institut de Recherches sur les Maladies de l'Appareil Digestif and by Association Charles Debray. F.B. was the recipient of a grant from the Fondation pour la Recherche Médicale.

0022-3565/00/2942-0466$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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