Seven Transmembrane-spanning Receptors: Structure and Function

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Because of its pre-eminent role in the most common diseases of the thyroid gland including Graves Disease, Thyroid Eye Disease and Thyroid Cancer, my laboratory group has decided to concentrate on study of the thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR). To define the structure-function relationships of TSHRs in normal physiology and in the pathophysiology of the afore-mentioned diseases with a long-term goal to delineate the mechanism(s) of signaling by TSHRs and of developing probes/drugs targeted at TSHRs. TSHR is a member of the seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) super-family that is the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. TSHR is important per se and also serves as a model for all 7TMRs. During this year, we studied several new aspects of the function and structure of TSHRs. 1) We extended our studies into the molecular mechanisms involved in the pathogenesis of Thyroid Eye Disease TED. One prominent extra-thyroidal cell type that expresses TSHRs and is involved in Thyroid Eye Disease (TED or Graves' ophthalmopathy, GO) is the fibroblast/pre-adipocyte present in the retro-orbital space. TED is a troublesome component of Graves' disease (GD) that occurs in 25% of GD patients and can lead to blindness. At present, there is only a single Food and Drug Administration-approved medical therapy for TED that is targeted at the insulin-like growth factor type 1 receptor (IGF-1R). Major mediators of TED are auto-antibodies that are activators of TSHRs (TSAbs) on retro-orbital fibroblasts. We study activation of these cells primarily in tissue culture in cells obtained from TED patients at decompression surgery (GOFs). As it appears that the IGF-1R is involved in TED pathogenesis, there is an ongoing controversy as to whether, in addition to TSAbs, there are also auto-antibodies that stimulate IGF-1Rs in TED patients. We showed that the activation of GOFs by autoantibodies from patients with TED occurs via activation of TSH-Rs that in turn activate IGF1Rs via receptor crosstalk. We had previously shown that TSHR/IGF-1R crosstalk is an important component of the mechanism of GO pathogenesis, is mediated by -arrestin 1 acting as a scaffold to position TSH-R and IGF-1R within 40 nanometers of each other. These findings emphasize the importance of TSHRs as potential targets in TED therapy. Several research laboratories and pharmaceutical companies are pursuing this strategy. 2) We extended our studies of regulation of human thyroid cells by TSH. In contrast to many research groups that use animal thyroid cell lines, we use primary cultures of human thyrocytes because we have found important differences between rodent cell lines and human thyrocytes regarding TSH regulation. We showed that regulation of the genes involved in thyroid hormone biosynthesis in human thyroid cells in primary culture is biphasic. That is, low concentrations of TSH upregulates gene expression of thyroglobulin, thyroid peroxidase, deiodinase type 2, sodium-iodide symporter and TSH-R, and higher concentrations decrease them; this type of concentration (dose)-dependency has been termed regulation that exhibits an inverted U-shaped dose-response curve (IUDRC). An IUDRC has been found to increase the complexity and sensitivity of cellular regulation. We proposed that this is an important cell-autonomous mechanism to limit hyperstimulation of thyrocytes and maintain the euthyroid state in humans. Furthermore, we showed that the IUDRC for regulation by TSH is dependent on homodimerization of TSHRs. 3) We were involved in a clinical study of a patient with Graves dermopathy and TED in order to learn more of the differential regulation by TSH of extrathyroidal TSHRs. 4) Lastly, we were invited to author a Chapter on TSH and TSHR signaling for the upcoming issue of the most highly regarded DeGroot Textbook of Endocrinology.