The human growth hormone (hGH) antagonist G120RhGH does not antagonize GH in the rat, but has paradoxical agonist activity, probably via the prolactin receptor

Endocrinology
Agneta ModeI C Robinson

Abstract

Human GH (hGH) acts by dimerizing two hGH receptors that bind to different sites in hGH. G120RhGH, an analog mutated in the second binding site to prevent receptor dimerization, acts as an antagonist in vitro. We have now tested the activity of this analog in vivo in rats with low or absent endogenous GH secretion. Surprisingly, treatment with G120RhGH failed to antagonize the effects of infusions or injections of hGH in hypophysectomized (Hx) rats and had little effect on hepatic GH-sensitive CYP2C transcripts in GH-deficient dwarf (dw) rats. Paradoxically, G120RhGH stimulated skeletal growth when infused into Hx rats; a pulsatile iv infusion was more effective than a continuous pattern. Coinfusion of G120RhGH with hGH produced an additive effect on growth. In addition, continuous, but not pulsatile, G120RhGH infusion elevated hepatic 2C12 messenger RNA (mRNA) expression and reduced 2C11 mRNA expression in Hx rats. The direct effects of G120RhGH on hepatic CYP2C transcripts were confirmed in cultured hepatocytes in vitro, which also revealed a significant action of PRL in elevating 2C12 mRNA expression. Binding studies revealed that G120RhGH bound preferentially to hepatic PRL receptors, as [125I]G120hGH was completely displac...Continue Reading

Citations

Jan 26, 2008·Journal of Mammary Gland Biology and Neoplasia·Estelle TalletVincent Goffin
Sep 16, 2000·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·M J Thomas
Sep 17, 2013·Molecular and Cellular Endocrinology·John J KopchickDarlene E Berryman
Feb 5, 2008·Journal of Mammary Gland Biology and Neoplasia·Charles V ClevengerFeng Fang
Dec 28, 1999·Journal of Molecular Recognition : JMR·S N Behncken, M J Waters
Apr 9, 2005·Endocrine Reviews·Vincent GoffinPaul A Kelly
Jun 26, 2003·The Journal of Biological Chemistry·Sophie BernichteinVincent Goffin

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