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ATP-Independent Luminal Oscillations and Release of Ca²⁺ and H⁺ from Mast Cell Secretory Granules: Implications for Signal Transduction

Ivan Quesada^*, Wei-Chun Chin and Pedro Verdugo^*

^* Department of Bioengineering and Friday Harbor Laboratories, University of Washington, Seattle, Washington 98195; and Department of Chemical Engineering, FAMU/FSU, Tallahassee, Florida 32310-6046

Correspondence: Address reprint requests to Prof. P. Verdugo, Friday Harbor Laboratories, University of Washington, 620 University Rd., Friday Harbor, WA 98250. E-mail: verdugo{at}u.washington.edu.

InsP₃ is an important link in the intracellular information network. Previous observations show that activation of InsP₃-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 InsP₃ can also turn mast cell granules into proton oscillators. InsP₃-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 InsP₃-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.

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