Seven Transmembrane-spanning Receptors: Structure and Function

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of cell-surface, 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. We have used TSHRs as model 7TMRs to study 7TMR structure and function and, more recently, to specifically study the role of TSHRs in human disease. Both GH, which is the most common form of clinical hyperthyroidism, and TED are mediated primarily by autoantibodies that activate TSHRs. Since there are important differences in the effects of TSHR activation in engineered cells compared to cells in which TSHRs are endogenously expressed, and in human and non-human cells, we decided to study TSHRs in primary cultures of human thyroid cells and in cells in primary culture taken from the retro-orbital space of patients with TED at decompression surgery. (We refer to these cells as Graves orbital fibroblasts GOFs.) TSHR is the major regulator of thyroid gland function and is expressed in extra-thyroidal cells/tissues also. One prominent extra-thyroidal cell type that expresses TSHRs, which is involved in the pathogenesis of TED, is the fibroblast/pre-adipocyte present in the retro-orbital space. TED occurs in 25% of Graves Disease patients and can lead to blindness. There is only a single medical therapy currently approved to treat TED teprotumumab (TepezzaR), which is a monoclonal antibody that inhibits activation of the insulin-like growth factor-1 receptor (IGF1R). However, teprotumumab also inhibits signaling by the insulin receptor and thereby leads to hyperglycemia in a significant number of patients. We previously showed that maximal activation of GOFs required interactions between TSHRs and IGF1Rs. This type of interaction has been termed receptor crosstalk. During the past year, we showed that the mechanism of action of teprotumumab to treat TED is that it inhibits the activation of IGF1Rs that crosstalk with TSHRs activated by TSHR-activating autoantibodies (1). As predicted previously, we showed that autoantibody preparations from different patients with Graves disease showed distinct activation profiles in human thyroid cells and in GOFs (2). These observations explain in part why some patients exhibit GH, some exhibit TED and some exhibit both GH amd TED. During the past year, we extended our studies into the actions of TSH in human thyroid cells. Specifically, we showed that upregulation of thyroglobulin and thyroid peroxidase, two proteins involved in thyroid hormone synthesis, is dependent on TSHR internalization; that is, that some of the regulators that mediate transcription of these genes are activated by internalized TSHRs at an intracellular locus near the nucleus (3). The concept that 7TMRs can signal at the cell surface and at intracellular sites after internalization is a well-established phenomenon. Lastly, we were involved in a clinical study that showed that combined immunosuppressive therapy is an effective treatment of severe Graves dermopathy, a troublesome skin lesion (4). We plan to continue to study the roles of TSHR in normal physiology and in the pathogenesis of human disease with the goal to develop novel therapies for thyroid diseases.