Synaptotagmin 2 couples mucin granule exocytosis to Ca²⁺ signaling from endoplasmic reticulum

Synaptotagmin 2 (Syt2) functions as a low affinity, fast exocytic Ca²⁺ sensor in neurons, where it is activated by Ca²⁺ influx through voltage-gated channels. Targeted insertion of lacZ into the mouse syt2 locus reveals expression in mucin-secreting goblet cells of the airways. In these cells, rapid Ca²⁺ entry from the extracellular medium does not contribute significantly to stimulated secretion (Davis, C. W., and Dickey, B. F. (2008) Annu. Rev. Physiol. 70, 487-512). Nonetheless, Syt2^-/- mice show a severe defect in acute agonist-stimulated airway mucin secretion, and Syt2^-/- mice show a partial defect. In contrast to Munc13-2^-/- mice (Zhu, Y., Ehre, C., Abdullah, L. H., Sheehan, J. K., Roy, M., Evans, C. M., Dickey, B. F., and Davis, C. W. (2008) J. Physiol. (Lond.) 586, 1977-1992), Syt2^-/- mice show no spontaneous mucin accumulation, consistent with the inhibitory action of Syt2 at resting cytoplasmic Ca²⁺ in neurons. In human airway goblet cells, inositol trisphosphate receptors are found in rough endoplasmic reticulum that closely invests apical mucin granules, consistent with the known dependence of exocytic Ca²⁺ signaling on intracellular stores in these cells. Hence, Syt2 can serve as an exocytic sensor for diverse Ca²⁺ signaling systems, and its levels are limiting for stimulated secretory function in airway goblet cells.