Controversial Constitutive TSHR Activity: Patients, Physiology, and In Vitro Characterization

Abstract

G protein-coupled receptors constitute a large family of transmembrane receptors, which activate cellular responses by signal transmission and regulation of second messenger metabolism after ligand binding. For several of these receptors it is known that they also signal ligand-independently. The G protein-coupled thyroid stimulating hormone receptor (TSHR) is characterized by a high level of constitutive activity in the wild type state. However, little is known yet concerning the physiological relevance of the constitutive wild type TSHR activity. Certainly, knowledge of the physiological relevance of constitutive wild type receptor activity is necessary to better understand thyroid physiology and it is a prerequisite for the development of better therapies for nonautoimmune hyperthyroidism and thyroid cancer. Based on a literature search regarding all published TSHR mutations, this review covers several mutations which are clearly associated with a hyperthyroidism-phenotype, but interestingly show a lack of constitutive activity determined by in vitro characterization. Possible reasons for the observed discrepancies between clinical phenotypes and in vitro characterization results for constitutive TSHR activity are reviewed. All current in vitro characterization methods for constitutive TSHR mutations are "preliminary attempts" and may well be revised by more comprehensive and even better approaches. However, a standardized approach for the determination of constitutive activity can help to identify TSHR mutations for which the investigation of additional signaling mechanisms would be most interesting to find explanations for the current clinical phenotype/in vitro discrepancies and thereby also define suitable methods to explore the physiological relevance of constitutive wild type TSHR activity.

BRAF-Activated Long Noncoding RNA Modulates Papillary Thyroid Carcinoma Cell Proliferation through Regulating Thyroid Stimulating Hormone Receptor

“…Thyroid stimulating hormone (TSH), also known as thyrotropin, is a pituitary hormone that stimulates the thyroid through binding to its receptor (TSHR). TSHR is found mainly on thyroid follicular cells and aberrant expression of TSHR may be involved in development of thyroid cancer as well as Grave’s disease [ 8 - 11 ].…”

Neonatal Graves-Basedow disease due to long-standing TRAb persistence following total thyroidectomy

“…Increasing amount of data were published regarding TSHR mutations/polimorphisms which are clearly associated with a hyperthyroidism-phenotype, however little is known yet concerning their pathophysiological relevance and the mechanisms by which they trigger or influeces the severity of the disease. Several Graves-Basedow disease susceptibility loci have been identified, including HLA-DRβ1-Arg74, CD40, CTLA-4, PTPN22, thyroglobulin (Tg), and mutations targeting different cAMP pathway genes, for example, phosphodiesterases or other G proteincoupled receptors (GPCRs) that may also contribute to hyperthyroidism (10,11).…”

TSHR as a therapeutic target in Graves’ disease

“…Unligated wild-type TSHR exhibits constitutive activity (23). This ligand – independent activity results in the stimulation of G proteins and the generation of cAMP.…”