Differential expression of the thyrostimulin subunits, glycoprotein  2 and  5 in the rat pituitary

Abstract

Two glycoprotein hormone subunits, (glycoprotein hormone a2-subunit GPA2) and (glycoprotein hormone b5-subunit GPB5) have been recently discovered which, when expressed in vitro, heterodimerize to form a new hormone called thyrostimulin. Thyrostimulin activates the thyroid-stimulating hormone receptor (TSHR) and has thyrotropic activity. Immunological studies have indicated that both subunits co-localize in pituitary cells. To explore the function of thyrostimulin in the rat, we have cloned rat GPA2 and GPB5, reconstituted the heterodimers in vitro, and confirmed that rat thyrostimulin activates TSHR with an affinity similar to that of TSH. In situ hybridization of the pituitary showed that while GPA2 is expressed in the anterior lobe, GPB5 is not detected in any of the lobes. A quantitative analysis showed that the co-localization of GPA2 and GPB5 is restricted in the rat to the eye and the testis. We found that GPB5 can be detected in the pituitary by quantitative-PCR, but at extremely low levels, 2000-fold lower than TSH b-subunit (GPBtsh). Furthermore, the levels of GPB5 remain constant during the estrus cycle, while those of GPA2 vary. Finally, we found that none of the thyrostimulin subunits was induced by TRH in pituitary cell culture. These data point at the thyrostimulin system as being functionally different to the TSH system.

The role of thyrostimulin and its potential clinical significance

“…Such a role may be observed in the human pituitary gland, where GPA2 and GPB5 co-localize (Nagasaki et al 2006). Interestingly, TSHR is also present on folliculo-stellate cells of the human anterior pituitary (Brokken et al 2005).…”

“…Interestingly, GPA2 does not heterodimerize with any of the other four known β subunits, whilst GPB5 does not heterodimerize with GPA1 (Nagasaki et al 2006). Even though, the GPA1 and GPA2 have only 35% primary sequence identity.…”

“…Finally, although both are produced in the adenohypophysis, diff erent cell types are speculated to be involved in this process; thyrotrophs produce TSH, whilst thyrostimulin is believed to be produced by corticotrophs and stored in the same granules as ACTH in humans (Okada et al 2006). Th e latter, though, is a subject of debate as no co-localization whatsoever has been found with ACTH or POMC expressing cells in rats, respectively Nagasaki et al 2006). Hence, it would be interesting to investigate the potential paracrine mechanism that provides the link between these two systems.…”

Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness

“…thyrostimulin; type II deiodinase; inflammation; thyroid hormone THE PUTATIVE GLYCOPROTEIN HORMONE thyrostimulin, comprising ␣2-(GPA2) and ␤5-(GPB5) subunits, has been reported to activate the thyroid-stimulating hormone (TSH) receptor (TSHR). Thyrostimulin does not play a major role in the classical feedback regulation of the hypothalamo-pituitarythyroid (HPT) axis, as GPB5 knockout (GPB5 Ϫ/Ϫ ) mice do not have an abnormal thyroid phenotype and transcription of GPB5 is not regulated by thyroid hormone or thyrotropin-releasing hormone (TRH) (14,20). Furthermore, we recently showed that deletion of Gpb5 in mice does not result in abnormal regulation of the HPT axis during hypothyroidism and thyrotoxicosis (24).…”

“…Thyrostimulin does not play a major role in the classical feedback regulation of the hypothalamo-pituitarythyroid (HPT) axis, as GPB5 knockout (GPB5 Ϫ/Ϫ ) mice do not have an abnormal thyroid phenotype and transcription of GPB5 is not regulated by thyroid hormone or thyrotropin-releasing hormone (TRH) (14,20). Furthermore, we recently showed that deletion of Gpb5 in mice does not result in abnormal regulation of the HPT axis during hypothyroidism and thyrotoxicosis (24).…”