Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor

Abstract

Human thyrotropin (TSH), luteotropin (LH), follitropin (FSH), and chorionic gonadotropin are members of the heterodimeric glycoprotein hormone family. The common alpha subunit forms noncovalent heterodimers with different beta subunits. Two novel human glycoprotein hormonelike genes, alpha2 (A2) and beta5 (B5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. Immunological analyses confirmed the heterodimerization of A2 and B5 in transfected cells and their colocalization in the anterior pituitary. Recombinant A2/B5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human TSH receptors, but not LH and FSH receptors, and showed high affinity to TSH receptors in a radioligand receptor assay. The heterodimer also stimulated cAMP production and thymidine incorporation by cultured thyroid cells and increased serum thyroxine levels in TSH-suppressed rats in vivo. This new heterodimeric glycoprotein hormone was named as thyrostimulin based on its thyroid-stimulating activity. The expression of thyrostimulin in the anterior pituitary known to express TSH receptors suggested a paracrine mechanism. The present discovery of a new ligand based on genomic approaches could facilitate the understanding of the physiological roles of extra-thyroid TSH receptor systems and the structural-functional basis of receptor signaling by related glycoprotein hormones.

Developmental tracing of luteinizing hormone β‐subunit gene expression using green fluorescent protein transgenic medaka (Oryzias latipes) reveals a putative novel developmental function

“…The presence of these proteins in invertebrates suggests that they could be an ancestral form of the glycoprotein hormones. In mammals, these have been found to dimerize and activate the thyroid stimulating hormone receptor, leading to the heterodimer being called thyrostimulin (TS; Nakabayashi et al, 2002). Their endogenous physiological function, however, remains to be elucidated.…”

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

“…They also identified a human homologue, called GPA2, of the common glycoprotein hormone ␣-subunit. Subsequently, it was shown that GPB5 and GPA2 heterodimerize and that the heterodimer activates the TSHR, and the term thyrostimulin was coined to describe the GPB5͞GPA2 heterodimer (10). Thus, the OGH Ϫ/Ϫ and OGH-TG mice have allowed us to investigate the physiological role of this active ␤-subunit in normal thyroid physiology, study its effects on various aspects of thyroid activity (TSH, T3͞T4, and thyroid histology), and identify key hormonal and metabolic perturbations that translate into important effects in regulation of body weight.…”

The role of thyrostimulin and its potential clinical significance

“…Th erefore, it is questionable whether it can, indeed, heterodimerize in the circulation (Dos Santos et al 2009). Th yrostimulin heterodimerizes only aft er treatment with a bifunctional reagent and it is likely that it may be less stable than other glycoprotein hormones (Shupnik et al 1989;Nakabayashi et al 2002). Nevertheless, GPB5 does have the Cys 120 -Cys 127 disulphide bridge, which corresponds to the sixth disulphide bridge (Cys 93 -Cys 100 ) in CGβ, crucial for hCG heterodimerization ( Figure 2) .…”