Role of protons in calcium signaling.

Thirty-six years after the publication of the important article by Busa and Nuccitelli on the variability of intracellular pH (pHi) and the interdependence of pHi and intracellular Ca2+ concentration ([Ca2+]i), little research has been carried out on pHi and calcium signaling. Moreover, the results appear to be contradictory. Some authors claim that the increase in [Ca2+]i is due to a reduction in pHi, others that it is caused by an increase in pHi. The reasons for these conflicting results have not yet been discussed and clarified in an exhaustive manner. The idea that variations in pHi are insignificant, because cellular buffers quickly stabilize the pHi, may be a limiting and fundamentally wrong concept. In fact, it has been shown that protons can move and react in the cell before they are neutralized. Variations in pHi have a remarkable impact on [Ca2+]i and hence on some of the basic biochemical mechanisms of calcium signaling. This paper focuses on the possible triggering role of protons during their short cellular cycle and it suggests a new hypothesis for an IP3 proton dependent mechanism of action.

Is hydrogen ion (H(+)) the real second messenger in calcium signalling?

Most second messengers have the acknowledged ability to mobilize the segregated Ca(2+) from intracellular stores, although the mechanisms of mobilization are unclear. To study this problem, the fact that inositol 1,4,5-trisphosphate, and six other known endogenous Ca(2+) mobilizers are acids, or acid-generating compounds, is highlighted. In physiological conditions, a newly generated acid releases H(+). The transient rise of H(+) in the cytosol may induce the lowering of pH, mobilization of bound Ca(2+), protein conformational rearrangement, store depletion, and Ca(2+) influx. Accordingly, a new description of the basic mechanism for signal transduction in non-excitable cells and the related consequences is put forward.