The inability to produce an adequate secretion of salivary fluid severely impacts general oral health, and the ability for effective speech, and mastication, resulting in conditions that constitute a major health problem for a significant proportion of the population. The focus of this project is to dissect, at the cellular and molecular level, the pathways involved in the effective regulation of salivary fluid secretion. Although the Ca2+- dependent activation of ion channels is the primary mechanism underlying the production of salivary fluid, secretion is significantly enhanced when both Ca2+ and cyclic AMP signaling systems are activated concurrently. Interestingly, cyclic AMP-dependent actions alone produce little or no secretion, but act to augment the normal Ca2+-dependent mechanisms. A significant component of this phenomenon is the potentiation of the Ca2+ signal per se by concomitant increases in cellular cyclic AMP levels. The underlying bases for this process will be examined in mouse parotid acinar cells by investigating - 1) the molecular basis for the cyclic AMP-dependent enhancement of intracellular Ca2+ release via the InsPS receptors;and 2) the characteristics and contributions of agonist-activated Ca2+ entry pathways in Ca2+ signaling, and their modulation by cyclic AMP. As a complement to these experimental studies, we will develop and utilize mathematical modeling approaches to help define the complex spatial and temporal interactions between these two signaling pathways by generating, in an interactive and cooperative manner, unique specific model predictions whose validity can then be tested experimentally. Understanding the molecular basis for this synergism is critical for fully understanding the normal physiology of the gland, and potentially providing key information for the ultimate manipulation of these processes as a means of improving fluid secretion in individuals with salivary hypofunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016999-05
Application #
7630529
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2005-09-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$346,817
Indirect Cost
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Shuttleworth, Trevor J (2012) STIM and Orai proteins and the non-capacitative ARC channels. Front Biosci (Landmark Ed) 17:847-60
Shuttleworth, Trevor J (2009) Arachidonic acid, ARC channels, and Orai proteins. Cell Calcium 45:602-10
Betzenhauser, Matthew J; Fike, Jenna L; Wagner 2nd, Larry E et al. (2009) Protein kinase A increases type-2 inositol 1,4,5-trisphosphate receptor activity by phosphorylation of serine 937. J Biol Chem 284:25116-25
Betzenhauser, Matthew J; Wagner 2nd, Larry E; Park, Hyung Seo et al. (2009) ATP regulation of type-1 inositol 1,4,5-trisphosphate receptor activity does not require walker A-type ATP-binding motifs. J Biol Chem 284:16156-63
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Zeller, S; Rudiger, S; Engel, H et al. (2009) Modeling of the modulation by buffers of Ca2+ release through clusters of IP3 receptors. Biophys J 97:992-1002
Gin, Elan; Falcke, Martin; Wagner, Larry E et al. (2009) Markov chain Monte Carlo fitting of single-channel data from inositol trisphosphate receptors. J Theor Biol 257:460-74
Betzenhauser, Matthew J; Wagner 2nd, Larry E; Iwai, Miwako et al. (2008) ATP modulation of Ca2+ release by type-2 and type-3 inositol (1, 4, 5)-triphosphate receptors. Differing ATP sensitivities and molecular determinants of action. J Biol Chem 283:21579-87
Park, Hyung Seo; Betzenhauser, Matthew J; Won, Jong Hak et al. (2008) The type 2 inositol (1,4,5)-trisphosphate (InsP3) receptor determines the sensitivity of InsP3-induced Ca2+ release to ATP in pancreatic acinar cells. J Biol Chem 283:26081-8
Betzenhauser, Matthew J; Wagner 2nd, Larry E; Won, Jong Hak et al. (2008) Studying isoform-specific inositol 1,4,5-trisphosphate receptor function and regulation. Methods 46:177-82

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