Extracellular Calcium Acts as a "Third Messenger" to Regulate Enzyme and Alkaline Secretion

It is generally assumed that the functional consequences of stimulation with Ca2+-mobilizing agonists are derived exclusively from the second messenger action of intracellular Ca2+, acting on targets inside the cells. However, during Ca2+signaling events, Ca2+moves in and out of the cell, causing changes not only in intracellular Ca2+, but also in local extracellular Ca2+. The fact that numerous cell types possess an extracellular Ca2+"sensor" raises the question of whether these dynamic changes in external [ Ca2+] may serve some sort of messenger function. We found that in intact gastric mucosa, the changes in extracellular [ Ca2+] secondary to carbachol-induced increases in intracellular [ Ca2+] were sufficient and necessary to elicit alkaline secretion and pepsinogen secretion, independent of intracellular [ Ca2+] changes. These findings suggest that extracellular Ca2+can act as a "third messenger" via Ca2+sensor(s) to regulate specific subsets of tissue function previously assumed to be under the direct control of intracellular Ca2+.