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J Biol Chem, Vol. 274, Issue 37, 26461-26468, September 10, 1999

Effect of Loss of P2Y₂ Receptor Gene Expression on Nucleotide Regulation of Murine Epithelial Cl Transport

From the Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina, Chapel Hill, North Carolina 27599

Extracellular nucleotides are believed to be important regulators of ion transport in epithelial tissues as a result of their ability to activate cell surface receptors. Although numerous receptors that bind nucleotides have been identified, the complexity of this receptor family, combined with the lack of pharmacological agents specific for these receptors, has made the assignment of particular receptors and ligands to physiological responses difficult. Because ATP and UTP appear equipotent and equieffective in regulating ion transport in many epithelia, we tested the hypothesis that the P2Y₂ receptor (P2Y₂-R) subtype mediates these responses in mouse epithelia, with gene targeting techniques. Mice with the P2Y₂-R locus targeted and inactivated (P2Y₂-R(/)) were generated, airways (trachea), gallbladder, and intestines (jejunum) excised, and Cl secretory responses to luminal nucleotide additions measured in Ussing chambers. Comparison of P2Y₂-R(+/+) with P2Y₂-R(/) mice revealed that P2Y₂-R mediated most (>85-95%) nucleotide-stimulated Cl secretion in trachea, about 50% of nucleotide responses in the gallbladder, and none of the responses in the jejunum. Dose-effect relationships for nucleotides in tissues from P2Y₂-R(/) mice suggest that the P2Y₆-R regulates ion transport in gallbladder and to a lesser extent trachea, whereas P2Y₄ and/or unidentified receptor(s) regulate ion transport in jejunum. We conclude that the P2Y₂ receptor is the dominant P2Y purinoceptor that regulates airway epithelial ion transport, whereas other P2Y receptor subtypes are relatively more important in other nonrespiratory epithelia.

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