Oscillations of pH inside the secretory granule control the gain of Ca²⁺ release for signal transduction in goblet cell exocytosis

Although Ca²⁺ plays a critical function in relaying intracellular messages, the role of subcellular organelles in the dynamics of intracellular Ca²⁺ still remains largely unexplored. We recently demonstrated that secretory granules can signal their own export from the cell by releasing Ca²⁺ to the cytosol. Oscillations and release of Ca²⁺ in/from the granule result from the combined action of a Ca²⁺/K⁺ ion exchange process that occurs in the granule's matrix, and the sequential activation of two Ca²⁺ -sensitive ion channels: an inositol 1,4,5-trisphosphate receptor Ca²⁺ channel (InsP₃R) and an apamin-sensitive Ca²⁺ -activated K⁺ channel (ASK_Ca). The results reported here from studies using isolated mucin granules indicate that intralumenal granular Ca²⁺ oscillations ([Ca²⁺]_L) and the corresponding cyclical release of Ca²⁺ to the cytosol induced by InsP₃ are accompanied by corresponding intragranular pH_G oscillations. Our data show that K⁺ -induced unbinding of Ca²⁺ from the mucin matrix increases as the pH_G declines. These observations suggest that oscillations of pH_G can modulate the gain of the Ca²⁺/ K⁺ ion exchange process, thereby controlling the amplitude of [Ca²⁺]_L oscillations and the granule-cytosol release gradient of [Ca²⁺].