Calcium can serve not only as an intracellular messenger, but also as an extracellular messenger controlling the gating properties of plasma membrane channels and acting as an agonist for G protein-coupled Ca(2+)-sensing receptors. Here we studied the potential extracellular messenger functions of this ion in anterior pituitary cells. Depletion and repletion of the extracellular Ca(2+) concentration ([Ca(2+)]e) induced transient elevations in the intracellular Ca(2+) concentration ([Ca(2+)]i), and elevations in [Ca(2+)]e above physiological levels decreased [Ca(2+)]i in somatotrophs and lactotrophs, but not in gonadotrophs. The amplitudes and duration of [Ca(2+)]i responses depended on the [Ca(2+)]e and its rate of change, which resulted exclusively from modulation of spontaneous voltage-gated Ca(2+) influx. Changes in [Ca(2+)]e also affected GH and PRL secretion. The PRL secretory profiles paralleled the [Ca(2+)]i profiles in lactotrophs, whereas GH secretion was also stimulated by [Ca(2+)]e independently of the status of voltage-gated Ca(2+) influx. [Ca(2+)]e modulated GH secretion in a dose-dependent manner, with EC(50) values of 0.75 and 2.25 mM and minimum secretion at about 1.5 mM. In a parallel experiment, cAMP accumulation progressively increased with elevation of [Ca(2+)]e, whereas inositol phosphate levels were not affected. These results indicate the cell type-specific role of [Ca(2+)]e in the control of Ca(2+) signaling and secretion.