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- Title
P2Y6 receptor mediates colonic NaCl secretion via differential activation of cAMP-mediated transport.
- Authors
Köttgen, Michael; Löffler, Thomas; Jacobi, Christoph; Nitschke, Roland; Pavenstädt, Hermann; Schreiber, Rainer; Frische, Sebastian; Nielsen, Søren; Leipziger, Jens
- Abstract
Extracellular nucleotides are important regulators of epithelial ion transport. Here we investigated nucleotide-mediated effects on colonic NaCl secretion and the signal transduction mechanisms involved. Basolateral UDP induced a sustained activation of Cl(-) secretion, which was completely inhibited by 293B, a specific inhibitor of cAMP-stimulated basolateral KCNQ1/KCNE3 K(+) channels. We therefore speculated that a basolateral P2Y(6) receptor could increase cAMP. Indeed UDP elevated cAMP in isolated crypts. We identified an epithelial P2Y(6) receptor using crypt [Ca(2+)](i) measurements, RT-PCR, and immunohistochemistry. To investigate whether the rat P2Y(6)elevates cAMP, we coexpressed the P2Y(1) or P2Y(6) receptor together with the cAMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel in Xenopus oocytes. A two-electrode voltage clamp was used to monitor nucleotide-induced Cl(-) currents. In oocytes expressing the P2Y(1) receptor, ATP transiently activated the endogenous Ca(2+)-activated Cl(-) current, but not CFTR. In contrast, in oocytes expressing the P2Y(6)receptor, UDP transiently activated the Ca(2+)-activated Cl(-) current and subsequently CFTR. CFTR Cl(-) currents were identified by their halide conductance sequence. In summary we find a basolateral P2Y(6) receptor in colonic epithelial cells stimulating sustained NaCl secretion by way of a synergistic increase of [Ca(2+)](i) and cAMP. In support of these data P2Y(6) receptor stimulation differentially activates CFTR in Xenopus oocytes.
- Publication
The Journal of clinical investigation, 2003, Vol 111, Issue 3, p371
- ISSN
0021-9738
- Publication type
Journal Article
- DOI
10.1172/JCI16711