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1 Institute of Physiology and Biophysics, The Water and Salt Research Center, University of Aarhus, Denmark
2 Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine, Université Libre de Bruxelles, Gosselies, Belgium
3 Laboratory of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Belgium
4 Laboratory of Physiopathology, School of Medicine, Université Libre de Bruxelles, Belgium
Extracellular nucleotides are important regulators of epithelial ion transport, frequently exerting their action from the luminal side. Luminal P2Y receptors have previously been identified in rat distal colonic mucosa. Their activation by UTP and ATP stimulates K+ secretion. The aim of this study was to clarify which of the P2Y receptor subtypes are responsible for the stimulated K+ secretion. To this end P2Y2 and P2Y4 knock-out mice were used to measure distal colonic ion transport in an Ussing chamber. In mouse (NMRI) distal colonic mucosa, luminal UTP and ATP with similar potency induced a rapid and transient increase of the transepithelial voltage (Vte) (UTP: from –0.81 ± 0.23 to 3.11 ± 0.61 mV, n
= 24), an increase of equivalent short circuit current (Isc) by 166.9 ± 22.8 µA cm–2 and a decrease of transepithelial resistance (Rte) from 29.4 ± 2.4 to 23.5 ± 2.0 
cm2. This effect was completely inhibited by luminal Ba2+ (5 mM, n
= 5) and iberiotoxin (240 nM, n
= 6), indicating UTP/ATP-stimulated K+ secretion. RT-PCR analysis of isolated colonic crypts revealed P2Y2, P2Y4 and P2Y6 specific transcripts. The luminal UTP-stimulated K+ secretion was still present in P2Y2 receptor knock-out mice, but significantly reduced (
Vte: 0.83 ± 0.26 mV) compared to wild-type littermates (Vte: 2.08 ± 0.52 mV, n
= 9). In P2Y4 receptor knock-out mice the UTP-induced K+ secretion was similarly reduced. Luminal UTP-stimulated K+ secretion was completely absent in P2Y2/P2Y4 double receptor KO mice. Basolateral UTP showed no effect. In summary, these results indicate that both the P2Y2 and P2Y4 receptors are present in the luminal membrane of mouse distal colonic mucosa, and stimulation of these receptors leads to K+ secretion.
(Received 24 November 2004;
accepted after revision 14 February 2005;
first published online 17 February 2005)
Corresponding author J. Leipziger: Ole Worms Allé 160, 8000 Aarhus C, Denmark. Email: leip{at}fi.au.dk
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