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J. Biol. Chem. 284 (8): 4815-4822

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Purinergic P2X7 Receptors Mediate ATP-induced Saliva Secretion by the Mouse Submandibular Gland*

Tetsuji Nakamoto{ddagger}§12, David A. Brown{ddagger}1, Marcelo A. Catalán{ddagger}1, Mireya Gonzalez-Begne{ddagger}, Victor G. Romanenko{ddagger}§, , and James E. Melvin{ddagger}§3

{ddagger}Center for Oral Biology and the §Department of Pharmacology & Physiology, University of Rochester Medical Center, Rochester, New York 14642

Abstract: Salivary glands express multiple isoforms of P2X and P2Y nucleotide receptors, but their in vivo physiological roles are unclear. P2 receptor agonists induced salivation in an ex vivo submandibular gland preparation. The nucleotide selectivity sequence of the secretion response was BzATP >> ATP > ADP >> UTP, and removal of external Ca2+ dramatically suppressed the initial ATP-induced fluid secretion (~85%). Together, these results suggested that P2X receptors are the major purinergic receptor subfamily involved in the fluid secretion process. Mice with targeted disruption of the P2X7 gene were used to evaluate the role of the P2X7 receptor in nucleotide-evoked fluid secretion. P2X7 receptor protein and BzATP-activated inward cation currents were absent, and importantly, purinergic receptor agonist-stimulated salivation was suppressed by more than 70% in submandibular glands from P2X7-null mice. Consistent with these observations, the ATP-induced increases in [Ca2+]i were nearly abolished in P2X7–/– submandibular acinar and duct cells. ATP appeared to also act through the P2X7 receptor to inhibit muscarinic-induced fluid secretion. These results demonstrate that the ATP-sensitive P2X7 receptor regulates fluid secretion in the mouse submandibular gland.

Received for publication November 12, 2008.

* This work was supported, in whole or in part, by National Institutes of Health Grants DE09692 and DE08921 (to J. E. M.) and NIDCR Training Grant T32-DE07202 (to D. A. B. and M. G.-B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 These authors contributed equally to this work.

2 Present address: Dept. of Oral Reconstruction and Rehabilitation, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu City 803-8580, Japan.

3 To whom correspondence should be addressed: Center for Oral Biology, Box 611, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-3441; Fax: 585-506-0190; E-mail: james_melvin{at}

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