ATP-independent luminal oscillations and release of Ca2+ and H+ from mast cell secretory granules:: Implications for signal transduction

InsP(3) is an important link in the intracellular information network. Previous observations show that activation of InsP(3)-receptor channels on the granular membrane can turn secretory granules into Ca2+ oscillators that deliver periodic trains of Ca2+ release to the cytosol (T. Nguyen, W. C. Chin, and P. Verdugo, 1998, Nature, 395: 908-912; I. Quesada, W. C. Chin, J. Steed, P. Campos-Bedolla, and P. Verdugo, 2001, Biophys. J. 80: 2133-2139). Here we show that InsP(3) can also turn mast cell granules into proton oscillators. InsP(3)-induced intralumenal [H+] oscillations are ATP-independent, result from H+/K+ exchange in the heparin matrix, and produce perigranular pH oscillations with the same frequency. These perigranular pH oscillations are in-phase with intralumenal [H+] but out-of-phase with the corresponding perigranular [Ca2+] oscillations. The low pH of the secretory compartment has critical implications in a broad range of intracellular processes. However, the association of proton release with InsP(3)-induced Ca2+ signals, their similar periodic nature, and the sensitivity of important exocytic proteins to the joint action of Ca2+ and pH strongly suggests that granules might encode a combined Ca2+/H+ intracellular signal. A H+/Ca2+ signal could significantly increase the specificity of the information sent by the granule by transmitting two frequency encoded messages targeted exclusively to proteins like calmodulin, annexins, or syncollin that are crucial for exocytosis and require specific combinations of [Ca2+] "and'' pH for their action.