THYROTROPIN, LIKE LUTEINIZING-HORMONE (LH) AND CHORIONIC-GONADOTROPIN (CG), INCREASES CAMP AND INOSITOL PHOSPHATE LEVELS IN CELLS WITH RECOMBINANT HUMAN LH/CG RECEPTOR

Glycoprotein hormones and their receptors are each structurally related; thus, ligand-receptor cross reactivity may exist in pathologic situations, i.e., high human chorionic gonadotropin (hCG) levels in patients has been suggested to activate the thyrotropin receptor (TSHR). Studies with Cos-7 cells transfected with human CG and TSH receptor cDNAs suggest the converse may be more likely. Thus, in cells with TSHR, about 3 × 10-11 and 3 × 10-10 M TSH cause half maximal increases in cAMP and inositol phosphate (IP) levels, respectively, whereas 10-6 M hCG has no effect on either. In cell with CGR, about 10-11 and 10-9 M CG or lutropin (LH) significantly increase cAMP and IP levels. Surprisingly, however, 10-11 and 10-9 M TSH are similarly effective in the two assays, respectively, and TSH increases cAMP and IP levels to the same extent as CG and LH. LH contamination of TSH is unlikely given similar results with highly purified TSH preparations from different sources, including recombinant TSH, and the specificity of simultaneously measured binding data. Thus, TSH binds with high affinity (K(d) = 7 x 10-11 M) to the human TSHR; hCG (up to 10-7 M) does not displace TSH binding. Similarly, hCG binds with high affinity (K(d) = 5 × 10-10 M) to the hCGR and TSH is only a weak inhibitor (K(i) = 1 × 10-8 M). Stimulating TSHR autoantibodies, with no epitopes on the CGR, do not duplicate GSH action. The unusual agonist action of TSH with recombinant CGR is consistent with TSHR models describing separate agonist and antagonist determinants; it may be a factor in the precocious puberty of juvenile hypothyroidism with high TSH levels. © 1993 Academic Press, Inc.