Anion secretion evoked by Pasteurella multocida toxin across rat colon

Abstract

Stimulation of muscarinic receptors is known to have a biphasic effect on colonic Cl − secretion: a short-lasting activation, which is followed by a long-lasting inhibition. In order to find out, which role G q proteins play in both processes, Pasteurella multocida toxin was used, a known activator of Gα q. This toxin (1.5 µg/ml) had a dual action on short-circuit current ( I sc) across rat distal colon: it stimulated transiently I sc and subsequently down-regulated the I sc evoked by Ca 2+-dependent secretagogues such as acetylcholine or ATP. The inactive mutant ( P. multocida toxin C1165S), which does not stimulate G α q, was ineffective. Cl − dependence and sensitivity against bumetanide, a blocker of the Na +–K +–2Cl − cotransporter, confirmed that the increase in I sc evoked by the toxin represented Cl − secretion. The effect of P. multocida toxin was suppressed by YM-254890 (10 − 7 M), a blocker of Gα q. Experiments with apically permeabilized tissues revealed that the secretory response to P. multocida toxin was concomitant with an increase in basolateral K + conductance as it is observed for other agonists inducing Ca 2+-dependent anion secretion. Consequently, these results suggest that G q proteins are not only involved in the activation of secretion, e.g. after stimulation of muscarinic or purinergic receptors, but also play a central role in the long-term down-regulation of intestinal secretion after activation of these types of receptors.