P2Y6 Receptor Mediates Colonic NaCl Secretion Via Differential Activation of CAMP-mediated Transport

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2003 Feb 6

PMID 12569163

Citations 27

Authors

Michael Kottgen

Thomas Loffler

Christoph Jacobi

Roland Nitschke

Hermann Pavenstadt

Rainer Schreiber

Sebastian Frische

Soren Nielsen

Jens Leipziger

Affiliations

Soon will be listed here.

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.

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References

Nicholas R, Watt W, Lazarowski E, Li Q, Harden K . Uridine nucleotide selectivity of three phospholipase C-activating P2 receptors: identification of a UDP-selective, a UTP-selective, and an ATP- and UTP-specific receptor. Mol Pharmacol. 1996; 50(2):224-9. View

Hwang T, Schwiebert E, Guggino W . Apical and basolateral ATP stimulates tracheal epithelial chloride secretion via multiple purinergic receptors. Am J Physiol. 1996; 270(6 Pt 1):C1611-23. DOI: 10.1152/ajpcell.1996.270.6.C1611. View

Suessbrich H, Bleich M, Ecke D, Rizzo M, Waldegger S, Lang F . Specific blockade of slowly activating I(sK) channels by chromanols -- impact on the role of I(sK) channels in epithelia. FEBS Lett. 1996; 396(2-3):271-5. DOI: 10.1016/0014-5793(96)01113-1. View

Jia Y, Mathews C, Hanrahan J . Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J Biol Chem. 1997; 272(8):4978-84. DOI: 10.1074/jbc.272.8.4978. View

Leipziger J, Kerstan D, Nitschke R, Greger R . ATP increases [Ca2+]i and ion secretion via a basolateral P2Y-receptor in rat distal colonic mucosa. Pflugers Arch. 1997; 434(1):77-83. DOI: 10.1007/pl00008079. View

Communi D, Boeynaems J . Receptors responsive to extracellular pyrimidine nucleotides. Trends Pharmacol Sci. 1997; 18(3):83-6. DOI: 10.1016/s0165-6147(96)01035-8. View

Communi D, Govaerts C, Parmentier M, Boeynaems J . Cloning of a human purinergic P2Y receptor coupled to phospholipase C and adenylyl cyclase. J Biol Chem. 1998; 272(51):31969-73. DOI: 10.1074/jbc.272.51.31969. View

Kerstan D, Gordjani N, Nitschke R, Greger R, Leipziger J . Luminal ATP induces K+ secretion via a P2Y2 receptor in rat distal colonic mucosa. Pflugers Arch. 1998; 436(5):712-6. DOI: 10.1007/s004240050693. View

Ralevic V, Burnstock G . Receptors for purines and pyrimidines. Pharmacol Rev. 1998; 50(3):413-92. View

10.

Somers G, Hammet F, Trute L, Southey M, Venter D . Expression of the P2Y6 purinergic receptor in human T cells infiltrating inflammatory bowel disease. Lab Invest. 1998; 78(11):1375-83. View

11.

Cressman V, Lazarowski E, Homolya L, Boucher R, Koller B, Grubb B . Effect of loss of P2Y(2) receptor gene expression on nucleotide regulation of murine epithelial Cl(-) transport. J Biol Chem. 1999; 274(37):26461-8. DOI: 10.1074/jbc.274.37.26461. View

12.

Schroeder B, Waldegger S, Fehr S, Bleich M, Warth R, Greger R . A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature. 2000; 403(6766):196-9. DOI: 10.1038/35003200. View

13.

Greger R . Role of CFTR in the colon. Annu Rev Physiol. 2000; 62:467-91. DOI: 10.1146/annurev.physiol.62.1.467. View

14.

Warth R, Bleich M . K+ channels and colonic function. Rev Physiol Biochem Pharmacol. 2000; 140:1-62. DOI: 10.1007/BFb0035550. View

15.

Leipziger J, MacGregor G, Cooper G, Xu J, Hebert S, Giebisch G . PKA site mutations of ROMK2 channels shift the pH dependence to more alkaline values. Am J Physiol Renal Physiol. 2000; 279(5):F919-26. DOI: 10.1152/ajprenal.2000.279.5.F919. View

16.

von Kugelgen I, Wetter A . Molecular pharmacology of P2Y-receptors. Naunyn Schmiedebergs Arch Pharmacol. 2000; 362(4-5):310-23. DOI: 10.1007/s002100000310. View

17.

Hollopeter G, Jantzen H, Vincent D, Li G, ENGLAND L, Ramakrishnan V . Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001; 409(6817):202-7. DOI: 10.1038/35051599. View

18.

Warny M, Aboudola S, Robson S, Sevigny J, Communi D, Soltoff S . P2Y(6) nucleotide receptor mediates monocyte interleukin-8 production in response to UDP or lipopolysaccharide. J Biol Chem. 2001; 276(28):26051-6. DOI: 10.1074/jbc.M102568200. View

19.

Bailey M, Imbert-Teboul M, Turner C, Kaila Srai S, Burnstock G, Unwin R . Evidence for basolateral P2Y(6) receptors along the rat proximal tubule: functional and molecular characterization. J Am Soc Nephrol. 2001; 12(8):1640-1647. DOI: 10.1681/ASN.V1281640. View

20.

Kunzelmann K, Mall M . Electrolyte transport in the mammalian colon: mechanisms and implications for disease. Physiol Rev. 2002; 82(1):245-89. DOI: 10.1152/physrev.00026.2001. View