In addition to the """"""""classic"""""""" neurotransmitters of the peripheral nervous system, acetylcholine and norepinephrine, roles in the regulation of exocrine gland function have been demonstrated in recent years for several other agents, including ATP and various neuropeptides, including vasoactive intestinal peptide (VIP). In salivary glands, much information has been obtained concerning neurotransmitter regulation of acinar cell function. However, due to the lack of suitable model systems, relatively little is known about neurotransmitter regulation of salivary gland duct cell function. Recently, morphological and biochemical data have been obtained which indicate that the HSG-PA cell line, of human submandibular gland ductal origin, possesses several important characteristics of normal duct cells and thus holds much promise as a model system for studying duct cell- specific functions and their regulation by neurotransmitters. Our studies to date have documented the presence in HSG-Pa cells of receptors for VIP, coupled to adenylyl cyclase, and for neurotensin and ATP, coupled to phospholipase C. Additional preliminary evidence demonstrates agonist- stimulated increases in K+ and C1- fluxes in response to one or more of these agents and alterations of these responses by osmotic challenge, in which exposure of cells to hypotonic medium results in a dramatic enhancement of neurotransmitter stimulated ion (K+) flux whereas hypertonic medium blocks the neurotransmitter-stimulated fluxes. This proposal focuses on neurotransmitter regulation of duct cell ion transport and the effects of osmotic changes on that regulation, using the HSG-PA cell line as a model. First, regulation by VIP, neurotensin and ATP of monovalent ion fluxes will be evaluated. Transcellular ion movements, studied in Ussing chambers, will measure agonist-induced changes in short circuit current in conjunction with radioisotope tracer and ion replacement experiments to identify the transported species. Receptor and non-receptor modulators of intracellular signaling pathways will be used to correlate changes in, and interactions of, second messengers with ion fluxes. Radioligand binding will be used to further characterize the receptors involved. The second area of investigation focuses on identification of the mechanisms by which changes in medium osmolarity modulate ion transport regulation by the neurotransmitters. Studies at discrete steps in the intracellular signaling processes (agonist binding to receptor; G protein involvement, second messenger production, activation of K+ flux) will be performed to define the points in the signaling pathway where osmotic challenges affect neurotransmitter regulation of K+ flux. Together, these studies promise to increase substantially our understanding of the roles of VIP, neurotensin and ATP in regulation of secretory processes in salivary duct cells and the role perturbations in the cells' osmotic environment have in regulation of transport by these neurotransmitters, thus helping to establish a foundation for evaluating the role of alterations in duct cell- specific functions and their regulation in various exocrine disease states.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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University of Missouri-Columbia
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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
Yelovitch, Shir; Barr, Haim M; Camden, Jean et al. (2012) Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist. J Med Chem 55:7623-35
Weisman, Gary A; Woods, Lucas T; Erb, Laurie et al. (2012) P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential. CNS Neurol Disord Drug Targets 11:722-38

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