Rescue of calcineurin A alpha null mice reveals a role for calcineurin in salivary gland function

Abstract

Calcineurin is a calcium‐dependent enzyme that functions in many cells including the immune system, neurons, musculature and kidney. The phenotype of mice lacking the αisoform of the catalytic subunit (CnAα‐/‐) is notable for failure to thrive and early lethality; a cause for which has yet to be identified. In this study we report the rescue of CnAα‐/‐ mice to adulthood by feeding of a modified diet. The success of this approach suggested a defect in salivary gland function. Accordingly, while the rate of salivary production was normal, there was a significant decline in salivary amylase and peroxidase activity and lower amounts of sialic acid, indicating a defect in exocrine vesicle formation. Consistent with this finding, salivary glands from null mice demonstrated a marked attenuation of secretory vesicles and granular content of serosal acinar cells in submandibular glands. Subcellular fractionation of wildtype salivary glands revealed endoplasmic reticulum (ER) and trans‐Golgi network expression and activity of the αisoform. Loss of CnAα leads to retention of secretory vesicles in these fractions. Moreover, calcineurin activity in fractions containing the αisoform can be upregulated by acetylcholine and blocked by xestospongin, demonstrating a requirement for the IP3R. In conclusion, we find a critical role for CnAα downstream of the IP3R that is required for post‐ ER trafficking of secretory vesicles.