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Am J Physiol Gastrointest Liver Physiol 275: G1274-G1281, 1998;
0193-1857/98 $5.00
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Vol. 275, Issue 6, G1274-G1281, December 1998

Cholinergic ion secretion in human colon requires coactivation by cAMP

M. Mall1,2, M. Bleich1, M. Schürlein2, J. Kühr2, H. H. Seydewitz2, M. Brandis2, R. Greger1, and K. Kunzelmann1

1 Physiologisches Institut, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg; and 2 Kinderklinik der Albert-Ludwigs-Universität Freiburg, D-79106 Freiburg, Germany

Cl- secretion in the colon can be activated by an increase of either intracellular Ca2+ or cAMP. In this study we examined a possible interdependence of the two second-messenger pathways in human colonic epithelium. When measured in a modified Ussing chamber, carbachol (CCH; 100 µmol/l, basolateral), via an increase in cytosolic Ca2+ concentration ([Ca2+]i), activated a transient lumen-negative equivalent short-circuit current (Isc) [change (Delta ) in Isc = -79.4 ± 7.5 µA/cm2]. Previous studies indicated that intracellular Ca2+ directly acts on basolateral K+ channels, thus enhancing driving force for luminal Cl- exit. Increased intracellular cAMP (by basolateral addition of 100 µmol/l IBMX and 1 µmol/l forskolin) activated a sustained lumen-negative current (Delta Isc = -42.4 ± 7.2 µA/cm2) that was inhibited by basolateral trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl&2-chromane (10 µmol/l), a blocker of KvLQT1 channels. In the presence of elevated cAMP, the CCH-activated currents were augmented (Delta Isc = 167.7 ± 32.7 µA/cm2), suggesting cooperativity of the Ca2+- and cAMP-mediated responses. Inhibition of endogenous cAMP production by indomethacin (10 µmol/l) significantly reduced CCH-activated currents and even reversed the polarity in 70% of the experiments. The transient lumen-positive Isc was probably due to activation of apical K+ channels because it was blocked by luminal Ba2+ (5 mmol/l) and tetraethylammonium (10 mmol/l). In the presence of indomethacin (10 µmol/l, basolateral), an increase of cAMP activated a sustained negative Isc. Under these conditions, CCH induced a large further increase in lumen-negative Isc (Delta Isc = -100.0 ± 21.0 µA/cm2). We conclude that CCH acting via [Ca2+]i can induce Cl- secretion only in the presence of cAMP, i.e., when luminal Cl- channels are already activated. The activation of a luminal and basolateral K+ conductance by CCH may be essential for transepithelial KCl secretion in human colon.

cystic fibrosis transmembrane conductance regulator; epithelial transport; potassium channels; Ussing chamber; microelectrodes; transepithelial voltage; carbachol


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