[en] The P2Y4 receptor is responsive to UTP in human and to ATP and UTP in rodents. With the aim of identifying its pharmacotherapeutic interest, we generated P2Y4-null mice by a classic gene targeting method. The proportion of genotypes was consistent with X-linked Mendelian transmission. Gene inactivation was checked by the complete disappearance of P2Y4 receptor
mRNA from liver, stomach, and intestine. The P2Y4-null mice had a grossly normal behavior, growth, and reproduction. Chloride secretion by the jejunal epithelium was assessed in Ussing
chambers by the measurement of the short circuit current in the presence of phlorizin. We show here that the UTP- and ATPinduced chloride secretory responses observed in wild-type
mice are abolished in P2Y4-null mice. This is the first clearcut demonstration of a biological role of the P2Y4 receptor
Robaye, B.; Université Libre de Bruxelles - ULB > Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine
Ghanem, E.; Université Libre de Bruxelles - ULB > Laboratory of Physiopathology, School of Medicine
Wilkin, F.; Université Libre de Bruxelles - ULB > Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine
Fokan, D.; Université Libre de Bruxelles - ULB > Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine
Van Driessche, W.; Université Catholique de Louvain - UCL > Department of Physiology
Schurmans, Stéphane ; Université Libre de Bruxelles - ULB > Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire
Boeynaems, J. M.; Université Libre de Bruxelles - ULB > Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine
Beauwens, R.; Université Libre de Bruxelles - ULB > Laboratory of Physiopathology, School of Medicine
Language :
English
Title :
Loss of nucleotide regulation of epithelial chloride transport in the jejunum of P2Y4-null mice
Publication date :
2003
Journal title :
Molecular Pharmacology
ISSN :
0026-895X
eISSN :
1521-0111
Publisher :
American Society for Pharmacology and Experimental Therapeutics, Bethesda, United States - Maryland
Volume :
63
Issue :
4
Pages :
777-783
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Fonds Forton, an Action de Recherche Concertée of the Communauté Française de Belgique, the Belgian Program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Federal Service for Science, Technology and Culture, grants of the Fonds de la Recherche Scientifique Médicale, and the Fonds Emile DEFAY
Atia F, Zeiske W, and Van Driessche W (1999) Secretory apical Cl- channels in A6 cells: possible control by cell Ca2+ and cAMP. Pflueg Arch Eur J Physiol 438:344-353.
Bachman ES, Dhillon H, Zhang C-Y, Cinti S, Bianco AC, Kobilka BK, and Lowell BB (2002) βAR signaling required for diet-induced thermogenesis and obesity resistance. Science (Wash DC) 297:843-845.
Bogdanov YD, Wildman SS, Clements MP, King BF, and Burnstock G (1998) Molecular cloning and characterization of rat P2Y4 nucleotide receptor. Br J Pharmacol 124:428-430.
Cantiello HF, Prat AG, Reisin IL, Ercole LB, Abraham EH, Amara JJF, Gregory RJ, and Ausiello DA (1994) External ATP and its analogs activate the cystic fibrosis transmembrane conductance regulator by a cyclic AMP-independent mechanism. J Biol Chem 269:11224-32.
Clarke LL, Grubb BR, Yankaskas JR, Cotton CU, McKenzie A, and Boucher RC (1994) Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr(-/-) mice. Proc Natl Acad Sci USA 91:479-483.
Communi D, Pirotton S, Parmentier M, and Boeynaems J-M (1995) Cloning and functional expression of a human uridine nucleotide receptor. J Biol Chem 270: 30849-30852.
Communi D, Paindavoine P, Place GA, Parmentier M, and Boeynaems J-M (1999) Expression of P2Y receptors in cell lines derived from the human lung. Br J Pharmacol 127:562-568.
Crane JK, Olson RA, Jones HM, and Duffey ME (2002) Release of ATP during host cell killing by enteropathogenic E. coli and its role as a secretory mediator. Am J Physiol 283:G74-G86.
Cressman VL, Lazarowski E, Homolya L, Boucher RC, Koller BH, and Grubb BR (1999) Effect of loss of P2Y2 receptor gene expression on nucleotide regulation of murine epithelial Cl- transport. J Biol Chem 274:26461-26468.
Cuffe JE, Bielfeld-Ackermann A, Thomas J, Leipziger J, and Korbmacher C (2000) ATP stimulates Cl- secretion and reduces amiloride-sensitive Na+ absorption in M-1 mouse cortical collecting duct cells. J Physiol (London) 524:77-90.
Egan ME, Glockner-Pagel J, Ambrose C, Cahill PA, Pappoe L, Balamuth N, Cho E, Canny S, Wagner CA, Geibel J, et al. (2002) Calcium-pump inhibitors induce functional surface expression of Delta F508-CFTR protein in cystic fibrosis epithelial cells. Nat Med 8:485-492.
Harper S, Webb TE, Charlton SJ, Ng LL, and Boarder MR (1998) Evidence that P2Y4 nucleotide receptors are involved in the regulation of rat aortic smooth muscle cells by UTP and ATP. Br J Pharmacol 124:703-710.
Huang P, Lazarowski ER, Tarran R, Milgram SL, Boucher RC, and Stutts J (2001) Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells. Proc Natl Acad Sci USA 98:14120-14125.
Jin J, Dasari VR, Sistare FD, and Kunapuli SP (1998) Distribution of P2Y receptor subtypes on haematopoietic cells. Br J Pharmacol 123:789-794.
Kalin N, Claab A, Sommer M, Puchelle E, and Tümmler B (1999) ΔF508CFTR protein expression in tissues from patients with cystic fibrosis. J Clin Investig 103:1379-1389.
Kellerman DJ (2002) P2Y2 receptor agonists A new class of medication targeted at improved mucociliary clearance. Chest 121:201S-205S
Knowles MR, Clarke LL, and Boucher RC (1991) Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis. N Engl J Med 325:533-538.
Lazarowski ER, Rochelle LG, O'Neal WK, Ribeiro CMP, Grubb BR, Zhang V, Harden TK, and Boucher RC (2001) Cloning and functional characterization of two murine uridine nucleotide receptors reveal a potential target for correcting ion transport deficiency in cystic fibrosis gallbladder. J Pharmacol Exp Ther 297:43-49.
McNamara N, Khong A, McKemy D, Caterina M, Boyer J, Julius D, and Basbaum C (2001) ATP transduces signals from ASGM1, a glycolipid that functions as a bacterial receptor. Proc Natl Acad Sci USA 98:9086-9091.
Marcus DC and Scofield MA (2001) Apical P2Y4 purinergic receptor controls K+ secretion by vestibular dark cell epithelium. Am J Physiol 281:C282-C289.
Matsuoka I, Ohkubo S, Kimura J, and Uezono Y (2002) Adenine nucleotide-induced activation of adenosine A2B receptors expressed in Xenopus laevis oocytes: involvement of a rapid and localized adenosine formation by ectonucleotidases. Mol Pharmacol 61:606-613.
Nguyen T, Erb L, Weisman GA, Marchese A, Heng HHQ, Garrad RC, George SR, Turner JT, and O'Dowd BF (1995) Cloning, expression and chromosomal localization of the human uridine nucleotide receptor gene. J Biol Chem 270:30845-30848.
Pierce NF, Carpenter CCj, Elliott HL, Greenough WB III (1971) Effects of prostaglandins, theophylline and cholera exotoxin upon transmucosal water and electrolyte movement in the canine jejunum. Gastroentrology 60:22-32.
Sage CL and Marcus DC (2002) Immunolocalization of P2Y4 and P2Y2 purinergic receptors in strial marginal cells and vestibular dark cells. J Membr Biol 185:103-115.
Satterwhite CM, Farrelly AM, and Bradley ME (1999) Chemotactic, mitogenic and angiogenic actions of UTP on vascular endothelial cells. Am J Physiol 276:H1091-H1097.
Steagall WK and Drumm ML (1999) Stimulation of cystic fibrosis transmembrane conductance regulator-dependent short-circuit current across ΔF508 murine intestines. Gastroenterol 116:1379-1388.
Stam NJ, Klomp J, van de Heuvel M, and Olijve W (1996) Molecular cloning and characterization of a novel orphan receptor (P2P) expressed in human pancreas that shows high structural homology to the P2U receptor. FEBS Lett 384:260-264.
Suarez-Huerta N, Pouillon V, Boeynaems J-M, and Robaye B (2001) Molecular cloning and characterization of the mouse P2Y4 nucleotide receptor. Eur J Pharmacol 416:197-202.
Webb TE, Henderson DJ, Robets JA, and Barnard EA (1998) Molecular cloning and characterization of the rat P2Y4 receptor. J Neurochem 71:1348-1357.