Sjögren's syndrome (SS) is an autoimmune disease that specifically targets exocrine glands, including salivary glands, and results in an impairment of secretory function. P2Y(2) nucleotide receptors for extracellular ATP and UTP are up-regulated in response to stress or injury in a variety of tissues including submandibular glands (SMGs) [Ahn JS, Camden JM, Schrader AM, Redman RS, Turner JT. Reversible regulation of P2Y(2) nucleotide receptor expression in the duct-ligated rat submandibular gland. Am J Physiol Cell Physiol 2000;279:C286-94; Hou M, Malmsjö M, Möller S, Pantev E, Bergdahl A, Zhai X-H, et al. Increase in cardiac P2X(1)- and P2Y(2)-receptor mRNA levels in congestive heart failure. Life Sci 1999;65:1195-206; Kishore BK, Wang Z, Rab H, Haq M, Soleimani M. Upregulation of P2Y(2) purinoceptor during ischemic reperfusion injury (IRI): possible relevance to diuresis of IRI. J Am Soc Nephrol 1998;9:581 (abstract); Koshiba M, Apasov S, Sverdlov V, Chen P, Erb L, Turner JT, et al. Transient up-regulation of P2Y(2) nucleotide receptor mRNA expression is an immediate early gene response in activated thymocytes. Proc Natl Acad Sci U S A 1997;94:831-6; Turner JT, Landon LA, Gibbons SJ, Talamo BR. Salivary gland P2 nucleotide receptors. Crit Rev Oral Biol Med 1999;10:210-24; Seye CI, Gadeau AP, Daret D, Dupuch F, Alzieu P, Capron L, et al. Overexpression of the P2Y(2) purinoceptor in intimal lesions of the rat aorta. Arterioscler Thromb Vasc Biol 1997;17:3602-10; Seye C, Kong Q, Erb L, Garrad RC, Krugh B, Wang M, et al. Functional P2Y(2) nucleotide receptors mediate uridine 5'-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. Circulation 2002;106:2720-6].To assess whether P2Y(2) receptor expression is up-regulated in SMGs of the NOD.B10 mouse model of primary SS as compared to SMGs of normal C57BL/6 mice.SMG cells were isolated from normal C57BL/6 and diseased NOD.B10 mice. P2Y(2) receptor mRNA expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization, whereas functional P2Y(2) receptor activity was analyzed by measuring UTP-induced increases in [Ca(2+)](i).In contrast to SMG cells from C57BL/6 mice, SMG cells from 4- to 19-week-old NOD.B10 mice exhibited increased P2Y(2) receptor mRNA localized to both ductal and acinar cell types. The levels of mRNA for other uridine nucleotide receptors, i.e., P2Y(4) and P2Y(6) receptors, showed no significant differences between SMG cells of C57BL/6 and NOD.B10 mice, suggesting that only the P2Y(2) receptor was up-regulated in NOD.B10 mice. Moreover, P2Y(2) receptor activity in SMG cells from NOD.B10 mice increased with age (i.e., disease progression).P2Y(2) receptor up-regulation in SMGs is associated with the SS phenotype in NOD.B10 mice, which encourages further attempts to determine the role of this pathway in the development of SS.