Although GABA(C) receptors play a crucial role in the mammalian central nervous system, their functional expression in peripheral tissues has not yet been studied. Using the gut neuroendocrine tumor cell line STC-1 as a model, we provide first evidence for the functional expression of GABA(C) receptors in the gut: mRNAs of the GABA(C) receptor subunits rho1 and rho2 were detected in STC-1 cells by reverse transcription polymerase chain reaction (RT-PCR). Applying anti-rho-antibodies, specific immunostaining for GABA(C) receptors was observed. For functional characterization, the effects of GABA(C) receptor activation on [Ca2+]i and hormone secretion were studied. The selective GABA(C) receptor agonist cis-4-aminocrotonic acid (CACA) induced dose-dependent increases both of [Ca2+]i and of hormone (cholecystokinin) secretion. The stimulatory effects of CACA were antagonized by the GABA(C) receptor blockers (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and 3-aminopropyl(methyl)phosphinic acid (3-APMPA). These results demonstrate that GABA(C) receptors play an important role in neuroendocrine gastrointestinal secretion.