Project Summary Saliva is essential for several biological functions that are instrumental in maintaining oral health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction. Although saliva secretion is driven by concerted activities of several ion channels and transporters, the molecular mechanism involved in stimulated saliva secretion is not clearly understood. It has been suggested that Ca2+ plays a central role that regulates fluid secretion; however, information regarding the identity of the Ca2+ channels as well as the mechanism of regulation of these channels in salivary glands is not well understood. Moreover, in salivary gland dysfunction, such as primary Sjogren's syndrome (pSS) patients the acinar tissues appear to be normal but fail to function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that Ca2+ channels might be altered in this pathological condition. Results obtained from our awarded grant indicate that TRPC1 is the primary Ca2+ channel in salivary glands and is intimately involved saliva secretion. To understand the regulation of TRPC1 channel we have shown that TRPC1 is regulated through a complex protein-protein interaction. Furthermore, these interactions were confined to specific domains in the plasma membrane, but the protein that anchors these complexes is not clear. Therefore, in this renewal we intend to thoroughly characterize the role of cytosolic Ca2+ in salivary gland function and to determine the relationship between TRPC1 and salivary gland dysfunctions. The objective of this competitive renewal is to elucidate the Ca2+ signaling mechanism(s) in salivary gland dysfunction and establish the role of TRPC1 in pSS. This renewal application is based on the hypothesis that loss of TRPC1-mediated Ca2+ influx induces ER stress, promotes immune infiltration that leads to salivary gland destruction. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in salivary gland dysfunction as well as ways to restore functional salivary glands. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions.