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 Gq proteins play in both processes, Pasteurella multocida toxin was used, a known activator of Gαq. This toxin (1.5  µg/ml) had a dual action on short-circuit current (Isc) across rat distal colon: it stimulated transiently Isc and subsequently down-regulated the Isc evoked by Ca2+-dependent secretagogues such as acetylcholine or ATP. The inactive mutant (P. multocida toxin C1165S), which does not stimulate Gαq, was ineffective. Cl− dependence and sensitivity against bumetanide, a blocker of the Na+-K+-2Cl− cotransporter, confirmed that the increase in Isc evoked by the toxin represented Cl− secretion. The effect of P. multocida toxin was suppressed by YM-254890 (10− 7 M), a blocker of Gαq. 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 Gq 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.