Somatostatin, a hormone that signals via G(i)/G(o), usually inhibits increases in intracellular calcium concentration ([Ca(2+)](i)) and insulin release from beta-cells. We have found that in the presence of arginine vasopressin (AVP), which signals via G(q), somatostatin increased [Ca(2+)](i), leading to insulin release in HIT-T15 cells. The increase in [Ca(2+)](i) by somatostatin was observed even after 60 min of AVP treatment. Somatostatin alone failed to increase [Ca(2+)](i) and insulin release. Somatostatin induced changes in [Ca(2+)](i) in a biphasic pattern, characterized by a sharp and transient increase followed by a rapid decline to sub-basal levels. Pretreatment with pertussis toxin, which inactivates G(i)/G(o), abolished the effects of somatostatin. U-73122, an inhibitor of phospholipase C, antagonized the somatostatin-induced increase in [Ca(2+)](i). In Ca(2+)-free medium, somatostatin still increased [Ca(2+)](i). Depletion of intracellular Ca(2+) stores with thapsigargin, a microsomal Ca(2+)-ATPase inhibitor, abolished somatostatin's effect. In the presence of bradykinin, another G(q)-coupled receptor agonist, somatostatin also increased [Ca(2+)](i), but not in the presence of isoproterenol (a G(s)-coupled receptor agonist) or medetomidine (a G(i)/G(o)-coupled receptor agonist). Our findings suggest that somatostatin signals through G(i)/G(o), and involves phospholipase C and Ca(2+) release from the endoplasmic reticulum. The increase in [Ca(2+)](i) by somatostatin leads to insulin release. This cross-talk is specific to G(q) and G(i)/G(o), and is not limited to the AVP and somatostatin receptors.