title: Rescue of calcineurin Aα(-/-) mice reveals a novel role for the α isoform in the salivary gland.
abstract: 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 β isoform is required for T-cell development, α is important in the brain and kidney. In addition, mice lacking α but not β suffer from failure to thrive and early mortality. The purpose of this study was to identify the cause of postnatal death of calcineurin α null (CnAα(-/-)) mice and to determine the mechanism of α activity that contributes to the phenotype. CnAα(-/-) 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 α action. Data show that calcineurin is required for normal submandibular gland function and secretion of digestive enzymes. Loss of α 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.
authors: Atlanta Veterans Administration Medical Center, Decatur, GA 30322-0001, USA.
authors: Ramesh N
authors: RN
authors: Reddy
authors: Juan A
authors: JA
authors: Pena
authors: Brian R
authors: BR
authors: Roberts
authors: Stephen R
authors: SR
authors: Williams
authors: S Russ
authors: SR
authors: Price
authors: Jennifer L
authors: JL
authors: Gooch
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms; D021381:Protein Transport; D012469:Salivary Glands / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D008156:Luciferases; D019703:Calcineurin; C525673:PPP3CA protein, human