Anion secretion evoked by Pasteurella multocida toxin across rat colon

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 G alpha(q). This toxin (1.5 mu g/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 Ca2+-dependent secretagogues such as acetylcholine or ATP. The inactive mutant (P. multocida toxin C1165S), which does not stimulate G(q)(alpha) 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 G(q)(alpha), 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 Ca2+-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. (C) 2008 Elsevier B.V. All rights reserved.