DESCRIPTION: 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.