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.