The function of the cloned rat calcitonin receptors, C1a and C1b, was studied in Xenopus oocytes using the two-electrode voltage clamp method. In oocytes expressing the C1a receptors and the cystic fibrosis transmembrane conductance regulator (CFTR), C1a/ CFTR, application (30 sec) of either salmon calcitonin (sCT) or human calcitonin (hCT) activated currents through CFTR. In C1b/CFTR, sCT activated the currents, whereas hCT failed to elicit a response. The sCT induced currents in C1a/CFTR were similar in size to those in C1b/CFTR. Both the activation and the deactivation of sCT-induced currents were slower in C1a/ CFTR. In oocytes expressing C1a or C1b alone, application of relatively high concentrations of sCT induced small oscillatory inward currents. Application of hCT induced small inward currents in C1a alone, but failed to activate currents in C1b alone. These results demonstrate new insights into the signal transduction of calcitonin receptors.