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+].