Glucose-stimulated insulin secretion and -cell growth are important facets of pancreatic islet -cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein Gz and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic -cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which Gz impacts are intact in -cells, and Gz activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) -cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E1 (PGE1) is pertussis-toxin insensitive, indicating that other Gi family members are not involved in this process in this -cell line. Indeed, overexpression of a selective deactivator of Gz, the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucose-stimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by siRNA-mediated knockdown of Gz expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13)-cell line couples to Gz predominantly, and perhaps even exclusively. These data provide the first evidence for Gz signaling in pancreatic -cells, and identify an endogenous receptor-mediated signaling process in cells that is dependent on Gz function.