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 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 TRH receptors (TRH-R) and TSH receptors (TSH-R) as model 7TMRs to study their structure and function. During this year, we studied several new aspects of the structure and function of TSH-Rs. 1) An important observation for TSH-Rs is that they are expressed on cells other than the thyrocyte but the role(s) of TSH-R in these cells is not well understood. One prominent cell that expresses TSH-Rs that is involved in thyroid eye disease (Graves' ophthalmopathy, GO), which is a troublesome component of Graves' disease (GD) that occurs in 25% of GD patients but for which there is no medical therapy, is the fibroblast/pre-adipocyte present in the retro-orbital space. We study GO in cells in primary culture taken from the retro-orbital space of patients with GO at decompression surgery. We initially found a critical interaction between the TSH-R and the insulin-like growth factor 1 receptor (IGF-1R) in these cells and showed that this interaction (cross talk) allowed for a synergistic activation of GOFs. We have now shown that this cross-talk is mediated, in part, by synergistic activation of extracellular signal-regulated kinases. 2) It was proposed by others that there may be immunoglobulins (auto-antibodies; GO-Igs) in the blood of GO patients that can bind to and activate TSH-Rs and IGF-1Rs. We have now provided new evidence that there are no auto-antibodies that directly bind to and activate IGF-1R signaling. Nevertheless, we showed that inhibition of IGF-1R signaling may have a beneficial role in GO treatment. (This idea was recently confirmed in a study in patients with GO.) Our observations allow for the definitive conclusion that IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO. 3) We collaborated on a project that showed for the first time that TSH stimulates de novo synthesis of tri-iodothyronine (T3) in human thyrocytes. Previously it was thought that T3 is derived in thyrocytes only by de-iodination of thyroxine (T4). 4) We showed that T3 and glucose coordinately stimulate the expression of uncoupling protein 1 (UCP1) in brown adipocytes obtained from male mice. UCP1 is a critical protein in the function of brown adipocytes.