Activating mutations of TSH receptor

Mechanisms of activation of G protein-coupled receptor by the agonist, are supposed to rely on release from structural constraints, then allowing the "relaxed" receptor to activate the G protein. By analogy with experimental works on alpha1b adrenergic receptor, showing that mutations could result in constitutive activation of the receptor, it was hypothezised, that similar but spontaneous somatic mutations of the Thyrotropin-receptor could be the cause of thyroid toxic adenomas. This hypothesis has been confirmed. Furthermore, the rare cases of familial non autoimmune hyperthyroidism have been shown to be caused by germline mutations of Thyrotropin receptor, as well as the cases of non autoimmune neonatal hyperthyroidism. Beside the constitutive activation of the Thyrotropin-receptor a case of sensitization of the Thyrotropin-receptor to hCG by a mutation in the extracellular domain has been identified as the cause of familial gestational hyperthyroidism. All those mutation studies have been helpful in understanding the mechanisms of activation of glycoproteic hormones. A first model had been proposed, according to datas obtained from these mutations. In this model, the extracellular domain of the receptor exerts an inhibitory action on the transmembrane domain, and this interaction has to be disrupted to allow for activation of the receptor. However, recent experimental datas suggest that interaction between extracellular domain and transmembrane domain are more complex than just inhibitory, and that upon activation, the extracellular domain may convert from an inhibitory structure to an activating one.