Enhanced cAMP Accumulation by the Human Thyrotropin Receptor Variant with the Pro52Thr Substitution in the Extracellular Domain

Recently, a naturally occurring variant of the human thyrotropin receptor with a Pro52Thr substitution in the N‐terminal extracellular domain of the receptor has been identified. To determine the functional significance of this substitution, cDNAs of wild‐type and variant thyrotropin receptors were stably expressed in Chinese hamster ovary cells. The Pro52Thr substitution did not affect synthesis and membrane localization of the receptor, as evidenced by 125I‐thyrotropin binding analysis to intact cells. The variant receptor and the wild‐type receptor were expressed in equivalent numbers and displayed identical binding affinity for thyrotropin. Strikingly, thyrotropin increased cAMP accumulation to a much greater extent in cells expressing the variant receptor as compared to the wild‐type receptor‐expressing cells. Basal and cholera toxin‐stimulated or forskolin‐stimulated cAMP levels were not different. It is concluded that the Pro52Thr substitution in the N‐terminal region of the human thyrotropin receptor produces a receptor protein with enhanced coupling to cAMP production. This naturally occurring hyperactive thyrotropin receptor may participate in hyperthyroidism of patients with Graves' disease.