Abstract
To examine the physiological roles of type 2 and type 3 inositol 1,4,5-trisphosphate receptors(IP3R2 and IP3R3) in vivo, we generated mice lacking these receptors, channels for intracellular calcium release. The double knockout caused severe hyposalivation, which resulted in difficulties in dry food intake leading to death shortly after the weaning period. A diet of wet mashed food could rescue the double mutants from the lethal phenotype. In these mice, pancreatic acinar cells were highly eosinophilic, suggesting that zymogen granules accumulated throughout the cytoplasm because of deficits in exocrine secretion. In fact, experiments using dissociated acinar cells demonstrated that secretion of digestive enzymes (such as amylase and lipase), in response to muscarinic acetylcholine receptor stimulation, was abolished in the double mutants. Despite a caloric intake no less than that of wild-type mice, the double mutants had reduced body weights and low serum glucose levels. Difficulties in food digestion caused by the failure of pancreatic exocrine secretion could account for the undernourishment phenotype seen in these mice. These abnormalities were not seen in single gene mutants for IP3R2 or IP3R3. Taken together, these results demonstrate that IP3R2 and IP3R3 play redundant but indispensable roles in exocrine secretion of the salivary glands and the pancreas, thus, in normal animal growth and survival. [Jpn J Physiol 55 Suppl:S134 (2005)]
