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 recep tor with a Pro52Thr substitution in the N-terminal extracellular domai n of the receptor has been identified. To determine the functional sig nificance of this substitution, cDNAs of wild-type and variant thyrotr opin receptors were stably expressed in Chinese hamster ovary cells. T he Pro52Thr substitution did not affect synthesis and membrane localiz ation of the receptor, as evidenced by I-125-thyrotropin binding analy sis to intact cells. The variant receptor and the wild-type receptor w ere expressed in equivalent numbers and displayed identical binding af finity for thyrotropin. Strikingly, thyrotropin increased cAMP accumul ation to a much greater extent in cells expressing the variant recepto r as compared to the wild-type receptor-expressing cells. Basal and ch olera toxin-stimulated or forskolin-stimulated cAMP levels were not di fferent. It is concluded that the Pro52Thr substitution in the N-termi nal region of the human thyrotropin receptor produces a receptor prote in with enhanced coupling to cAMP production. This naturally occurring hyperactive thyrotropin receptor may participate in hyperthyroidism o f patients with Graves' disease.