title: Constitutive activities in the thyrotropin receptor: regulation and significance.
abstract: The thyroid-stimulating hormone receptor (TSHR, or thyrotropin receptor) is a family A G protein-coupled receptor. It not only binds thyroid-stimulating hormone (TSH, or thyrotropin) but also interacts with autoantibodies under pathological conditions. The TSHR and TSH are essential for thyroid growth and function and thus for all thyroid hormone-associated physiological superordinated processes, including metabolism and development of the central nervous system. In vitro studies have found that the TSHR permanently stimulates ligand-independent (constitutive) activation of Gs, which ultimately leads to intracellular cAMP accumulation. Furthermore, a vast variety of constitutively activating mutations of TSHR-at more than 50 different amino acid positions-have been reported to enhance basal signaling. These lead in vivo to a "gain-of-function" phenotype of nonautoimmune hyperthyroidism or toxic adenomas. Moreover, many naturally occurring inactivating mutations are known to cause a "loss-of-function" phenotype, resulting in resistance to thyroid hormone or hyperthyrotropinemia. Several of these mutations are also characterized by impaired basal signaling, and these are designated here as "constitutively inactivating mutations" (CIMs). More than 30 amino acid positions with CIMs have been identified so far. Moreover, the permanent TSHR signaling capacity can also be blocked by inverse agonistic antibodies or small drug-like molecules, which both have a potential for clinical usage. In this chapter, information on constitutive activity in the TSHR is described, including up- and downregulation, linked protein conformations, physiological and pathophysiological conditions, and related intracellular signaling.
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address: gunnar.kleinau@charite.de.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
mesh_terms: D000818:Animals; D054314:Drug Inverse Agonism; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D011989:Receptors, Thyrotropin; D054852:Small Molecule Libraries
keywords: Basal activity; Constitutive activity; Inverse agonism; Thyroid-stimulating hormone receptor; Thyrotropin receptor