The proper functioning of salivary glands is essential to the maintenance of oral health. The list of identified extracellular agents implicated in regulating salivary gland secretion continues to increase. Recent additions include extracellular nucleotides, working through P2 purinoceptors. While a role for ligand-gated ion channel P2 receptors in salivary glands has been known for several years, the presence and activity of G protein-coupled (GPC) P2 receptors in the glands has been less easily documented, although these receptors are present in cell lines of salivary origin. The studies proposed in this application are based on our recent cloning and expression of the first cDNA for a human P2 purinoceptor, the GPC P2U subtype and on initial studies of P2 receptor activity in normal rat submandibular gland (SMG) cells. The hypothesis to be tested is that the GPC P2 purinoceptor subtypes, P2U and P2Y, are involved in the regulation of salivary gland secretion and that the expression and activity of these receptors vary as a function of the state of development and organization of the glands and as a consequence of exposure to agonist. It is also hypothesized that rat SMG cells express volume-sensitive chloride channels that are involved in the regulatory volume decrease potentiated by P2 receptor agonists in cells of salivary origin.
The specific aims are: 1) to assess development-related changes in the expression and regulatory role of P2U and P2Y purinoceptors in rat salivary glands, using gland cells isolated from animals of different ages; 2) to examine the effects of disruption of normal salivary gland structure on P2U and P2Y receptor expression and activity; 3) to characterize agonist-induced desensitization of P2 receptors and to evaluate the role in desensitization of consensus phosphorylation sites within these receptors; and 4) to evaluate, through cloning and expression of its cDNA, the contribution of volume-sensitive chloride channels in HSG-PA salivary cells to regulatory volume decrease (RVD), a process potentiated by P2U receptor activation. Together, these studies will provide a fuller appreciation of the role that P2 receptors play in the regulation of salivary secretion and of the factors involved in the expression and activity of these receptors. The ultimate goal is to elucidate the contributions salivary P2 receptors make to the maintenance of oral health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE007389-14
Application #
2896988
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1992-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Woods, L T; Camden, J M; Khalafalla, M G et al. (2018) P2Y2 R deletion ameliorates sialadenitis in IL-14?-transgenic mice. Oral Dis 24:761-771
Voynova, Elisaveta; Mahmoud, Tamer; Woods, Lucas T et al. (2018) Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways. Immunohorizons 2:54-66
Kayes, Timothy Daniel; Weisman, Gary A; Camden, Jean M et al. (2016) New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland. J Immunol 197:2119-30
Woods, Lucas T; Camden, Jean M; El-Sayed, Farid G et al. (2015) Increased Expression of TGF-? Signaling Components in a Mouse Model of Fibrosis Induced by Submandibular Gland Duct Ligation. PLoS One 10:e0123641
Nadel, Yael; Lecka, Joanna; Gilad, Yocheved et al. (2014) Highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5'-(? or ?)-thio-(?,?- or ?,?)-methylenetriphosphate scaffold. J Med Chem 57:4677-91
Weisman, Gary A (2014) Why do male mice spit soluble enzymes that hydrolyze extracellular nucleotides? Focus on ""Prostatic acid phosphatase is the main acid phosphatase with 5'-ectonucleotidase activity in the male mouse saliva and regulates salivation"". Am J Physiol Cell Physiol 306:C997-8
Liao, Zhongji; Cao, Chen; Wang, Jianjie et al. (2014) The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells. J Biomed Sci Eng 7:1105-1121
El-Sayed, Farid G; Camden, Jean M; Woods, Lucas T et al. (2014) P2Y2 nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells. Am J Physiol Cell Physiol 307:C83-96
Erb, Laurie; Weisman, Gary A (2012) Coupling of P2Y receptors to G proteins and other signaling pathways. Wiley Interdiscip Rev Membr Transp Signal 1:789-803
Weisman, Gary A; Camden, Jean M; Peterson, Troy S et al. (2012) P2 receptors for extracellular nucleotides in the central nervous system: role of P2X7 and P2Yýýý receptor interactions in neuroinflammation. Mol Neurobiol 46:96-113

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