Extracellular calcium acts as a “third messenger” to regulate enzyme and alkaline secretion

It is generally assumed that the functional consequences of stimulation with Ca(2+)-mobilizing agonists are derived exclusively from the second messenger action of intracellular Ca(2+), acting on targets inside the cells. However, during Ca(2+) signaling events, Ca(2+) moves in and out of the cell, causing changes not only in intracellular Ca(2+), but also in local extracellular Ca(2+). The fact that numerous cell types possess an extracellular Ca(2+) “sensor” raises the question of whether these dynamic changes in external [Ca(2+)] may serve some sort of messenger function. We found that in intact gastric mucosa, the changes in extracellular [Ca(2+)] secondary to carbachol-induced increases in intracellular [Ca(2+)] were sufficient and necessary to elicit alkaline secretion and pepsinogen secretion, independent of intracellular [Ca(2+)] changes. These findings suggest that extracellular Ca(2+) can act as a “third messenger” via Ca(2+) sensor(s) to regulate specific subsets of tissue function previously assumed to be under the direct control of intracellular Ca(2+).