The distinct roles of alpha- and beta-subunits of human thyrotropin in the receptor-binding and postreceptor events.

The roles of alpha- and beta-subunits of human TSH (hTSH) were studied by investigating the inhibitory effects of monoclonal antibodies on the biological activity of hTSH. Four monoclonal antibodies directed toward different epitopes on the beta-subunit (hTSH beta) inhibited completely the receptor binding of hTSH to FRTL-5 rat thyroid cells. In contrast, five monoclonal antibodies directed toward different epitopes on the alpha-subunit had little or no effect on the receptor binding. Furthermore, four of five alpha-subunit-specific antibodies and three of four hTSH-specific antibodies inhibited both hTSH-induced cAMP accumulation and thymidine uptake in FRTL-5 cells, in a dose-response manner. One hTSH (alpha-beta heterodimer)-specific antibody which did not recognize the free subunits also had the inhibitory effect on both the receptor binding and hTSH-induced cAMP accumulation. These results strongly suggest that hTSH beta is indispensable for recognizing the receptors on FRTL-5 cells and that the alpha-subunit is required for signal transduction in postreceptor step(s). In addition, it is also suggested that the highly conformational structure of hTSH is absolutely essential for the biological activity.