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⁺.