Disease relevance of GHR

• However, in liver, GH-R, but not IGF-I or IGF-IR, mRNA levels were decreased in both IUGR groups [1].
• This suggests peripheral GH unresponsiveness, similar to protein-calorie malnutrition or GH receptor deficiency dwarfism, but mediated at a level distal to the hepatic GH receptor [2].

High impact information on GHR

• Abolition of this cortisol surge by fetal adrenalectomy prevented both the activation of exon 1A expression and the prepartum rise in GHR mRNA derived from the other leader exons in fetal ovine liver [3].
• Cortisol therefore appears to activate the adult mode of GHR gene expression in fetal ovine liver during late gestation [3].
• Hepatic GHR mRNA derived from leader exons other than 1A was detectable at 97 days and increased in abundance toward term in parallel with the normal prepartum rise in fetal plasma cortisol [3].
• Muscle IGF-I, but not GHR, mRNA abundance decreased with increasing gestational age in parallel with the prepartum rise in plasma cortisol [4].
• GH-R mRNA was localized in the trophectoderm, fetal mesoderm, and maternal uterine stroma [5].

Chemical compound and disease context of GHR

• In conclusion, the modest increases in circulating cortisol concentrations in IUGR fetuses did not increase hepatic GH-R mRNA expression and, therefore, do not explain the increased circulating IGF-I levels that we found with GH infusion, which are likely due to reduced clearance rather than increased production [1].

Biological context of GHR

• At least one transcript appears to be expressed in a liver-specific fashion, supporting a role for alternative RNA splicing in the tissue-specific regulation of sheep GH receptor expression [6].
• We demonstrate tissue-specific regulation of the somatotrophic axis in IUGR fetuses and a discontinuity between GH-R and IGF-I gene expression in GH-infused fetuses that is not explained by alterations in phosphorylated STAT5b [1].
• We hypothesized a cortisol-induced upregulation of fetal hepatic GH receptor (GH-R) mRNA levels, secondary increases in IGF-I mRNA levels, and circulating IGF-I levels, but a downregulation of the type I IGF receptor (IGF-IR) as an explanation [1].
• Expression of the adult liver-specific GHR mRNA transcript containing exon 1A was not detected earlier than 138 days of gestation (term 145 +/-2 days) [3].
• The up-regulation of related GHR proteins during the differentiation of mammary tissue supports the hypothesis that GH may act specifically via its own receptors [7].

Anatomical context of GHR

• In contrast, in placenta, GH-R, IGF-I, and IGF-IR expression were increased in IUGR vehicle-infused fetuses [1].
• Hence, using RNase protection assays and ovine riboprobes, expression of the IGF-I and growth hormone receptor (GHR) genes was examined in ovine skeletal muscle during late gestation and after experimental manipulation of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cortisol infusion [4].
• Immunoprecipitation of detergent-solubilized hepatic microsomal membranes from pregnant and fetal sheep using a panel of monoclonal antibodies raised against the extracellular region of the rabbit GHR showed potent immunological recognition of the [125I]oPL-receptor complexes [8].
• These findings show that thyroid hormones have an important role in the regulation of hepatic GHR and IGF-I gene expression in fetal sheep during late gestation and suggest that T(3) mediates the maturational effects of cortisol on the hepatic somatotropic axis close to term [9].
• This is the first report demonstrating the presence of mRNA for GHR in the choroid plexus [10].

Associations of GHR with chemical compounds

• However, increasing plasma T3 alone by an infusion of T3 for 5 days (8-12 microg x kg(-1) x day(-1) iv) in intact fetuses at this age had no effect on GHR or IGF-I gene expression in skeletal muscle [11].
• In Expt 2, prostaglandin F2 alpha (PGF2 alpha; 1 mumole) injected into the ovarian artery on day 11 or day 12 of the oestrous cycle had no effect on luteal concentrations of mRNA for either IGF-I or GH-R [12].

Physical interactions of GHR

• The fact that saturable binding could not be demonstrated for either GH or PRL with fetal liver microsomes contradicts recent suggestions that oPL is binding the GH receptor [13].

Other interactions of GHR

• GH infusion further increased placental GH-R and IGF-IR, but abolished the increase in IGF-I mRNA levels [1].
• The present study therefore examined the influence of maternal nutrient restriction (NR), targeted at specific periods of kidney development during early to mid gestation, on the mRNA abundance of receptors for glucocorticoid (GCR), growth hormone (GHR) and insulin-like growth factors-I (IGF-IR) and -II (IGF-IIR), and the IGF-I and -II ligands [14].
• However, the levels of GHR expression are markedly lower in fetal hepatic tissue compared to postnatal values, and there are conflicting data suggesting that ovine placental lactogen (oPL) and oGH share a common receptor [8].
• The ontogeny of hepatic growth hormone (GH) receptors (GHR), as measured by responses of both plasma insulin-like growth factor-I (IGF-I) and hepatic GHR to an exogenous bGH stimulus, was examined using sheep of different ages (Days 1-7, 14-21, 28-35, and 56-63 of life, and yearlings) [15].
• Conversely, 6-month-old offspring showed no difference in the abundance of either GH receptor or PRL receptor, while IGF-II mRNA was increased [16].

Analytical, diagnostic and therapeutic context of GHR

• GHR mRNA measured by Northern blot analysis was expressed at high levels in maternal liver at all gestational stages [17].
• Thyroidectomy at 105-110 days of gestation suppressed muscle GHR and IGF-I gene expression in fetuses studied at 127-130 and 142-145 days [11].
• RNA isolated from SCP cells was subjected to reverse transcription followed by PCR using a set of primers, designed on the basis of the ovine liver GHR sequence [10].
• Hypophysectomy also reduced the mean concentration of mRNA encoding GH-R to approximately 60% (P < 0.05) of the values in pituitary-intact ewes (days 5 or 12) [12].
• Using a new rabbit polyclonal antibody (7122A) directed against the recombinant extracellular domain of GH receptor (GHR-ECD) for western blot assays, we found two bands with apparent molecular weights of 70,000 and 50-60,000 Da in ovine mammary gland solubilized proteins [7].

References