The 5-HT3 receptor is a member of the Cys-loop family of ligand-gated ion channels, proteins that have been implicated in the pathology of several neurological disorders. In this study, we examine two mutations (R344H and P391R) that have been previously identified in individuals diagnosed with schizophrenia. These mutations are located in the M3-M4 loop of the 5-HT3 receptor and their occurrence presents the possibility that they contribute toward the etiology of this disorder. Radioligand binding with the 5-HT receptor antagonist, [3H]granisetron, revealed no significant difference in receptor affinity or density between mutant and wild-type receptors when expressed in HEK293 cells. However, comparison of EC50 values using whole-cell patch clamp for wild-type (1.68 microM +/- 0.01, n = 38), R344H (1.70 microM +/- 0.02, n = 18), and P391R (2.73 microM +/- 0.01, n = 8) receptors revealed a significant increase in the EC50 of the P391R mutant. Analysis of Hill co-efficients, and activation and desensitization rate constants showed no significant difference between wild-type and mutant receptors. These data suggest that the P391R, but not the R344H, mutation may play a role in the pathology of schizophrenia.