Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms.

The TSH receptor (TSHR) together with the homologous lutropin/choriogonadotropin receptor and the follitropin receptor are glycoprotein hormone receptors (GPHRs). They constitute a subfamily of the rhodopsin-like G protein-coupled receptors with seven transmembrane helices. GPHRs and their corresponding hormones are pivotal proteins with respect to a variety of physiological functions. The identification and characterization of intra- and intermolecular signaling determinants as well as signaling mechanisms are prerequisites to gaining molecular insights into functions and (pathogenic) dysfunctions of GPHRs. Knowledge about activation mechanisms is fragmentary, and the specific aspects have still not been understood in their entirety. Therefore, here we critically review the data available for these receptors and bring together structural and functional findings with a focus on the important large extracellular portion of the TSHR. One main focus is the particular function of structural determinants in the initial steps of the activation such as: 1) hormone binding at the extracellular site; 2) hormone interaction at a second binding site in the hinge region; 3) signal regulation via sequence motifs in the hinge region; and 4) synergistic signal amplification by cooperative effects of the extracellular loops toward the transmembrane region. Comparison and consolidation of data from the homologous glycoprotein hormone receptors TSHR, follitropin receptor, and lutropin/choriogonadotropin receptor provide an overview of extracellular mechanisms of signal initiation, conduction, and regulation at the TSHR and homologous receptors. Finally, we address the issue of structural implications and suggest a refined scenario for the initial signaling process on GPHRs.