Role of proton gradients and vacuolar H+-ATPases in the refilling of intracellular calcium stores in exocrine cells

Numerous hormones and neurotransmitters activate cells by increasing cytosolic calcium concentration ([Ca2+](i)), a key regulatory factor for many cellular processes. A pivotal feature of these Ca2+ signals is the release of Ca2+ from intracellular stores, which is followed by activation of extracellular calcium influx, allowing refilling of the stores by SERCA pumps associated with the endoplasmic reticulum. Although the mechanisms of calcium release and calcium influx have been extensively studied, the biology of the Ca2+ stores is poorly understood. The presence of heterogeneous calcium pools in cells has been previously reported [1-3]. Although recent technical improvements have confirmed this heterogeneity [4], knowledge about the mechanisms underlying Ca2+ transport within the stores is very scarce and rather speculative, A recent study in polarized exocrine cells [5] has revealed the existence of Ca2+ tunneling from basolateral stores to luminal pools, where Ca2+ is initially released upon cell activation. Here, we present evidence that, during stimulation, Ca2+ transported into basolateral stores by SERCA pumps is conveyed toward the luminal pools driven by proton gradients generated by vacuolar H+-ATPases. This finding unveils a new aspect of the machinery of Ca2+ stores.