Rescue of Calcineurin Aα-/- Mice Reveals a Novel Role for the α Isoform in the Salivary Gland

Calcineurin is an important signal transduction mediator in T cells, neurons, the heart, and kidneys. Recent evidence points to unique actions of the two main isoforms of the catalytic subunit. Although the beta isoform is required for T-cell development, alpha is important in the brain and kidney. In addition, mice lacking alpha but not beta suffer from failure to thrive and early mortality. The purpose of this study was to identify the cause of postnatal death of calcineurin alpha null (CnA alpha(-/-)) mice and to determine the mechanism of alpha activity that contributes to the phenotype. CnA alpha(-/-) mice and wild-type littermate controls were fed a modified diet and then salivary gland function and histology were examined. In vitro studies were performed to identify the mechanism of a action. Data show that calcineurin is required for normal submandibular gland function and secretion of digestive enzymes. Loss of alpha does not impair nuclear factor of activated T-cell activity or expression but results in impaired protein trafficking downstream of the inositol trisphosphate receptor. These findings show a novel function of calcineurin in digestion and protein trafficking. Significantly, these data also provide a mechanism to rescue to adulthood a valuable animal model of calcineurin inhibitor-mediated neuronal and renal toxicities. (Am J Pathol 2011, 178:1605-1613; DOI: 10.1016/j.ajpath.2010.12.054)