GH-binding proteins

The principal organs involved in the peripheral clearance of hGH from the plasma are the kidney and fiver. hGH is cleared via glomerular filtration at the kidney and by a receptor-mediated mechanism at the fiver (58,59). In animal models, derivatives of hGH such as the 20,000 mol wt variant, oligomeric forms, and hGH complexed with GH-binding protein have been shown to be cleared from the semm at significandy lower rates than 22,000 mol wt hGH (60—62). The prolonged plasma half-life of these derivatives probably reflects a combination of decreased receptor affinity and size constraints on glomerular filtration. 

Figure 8.13. Growth hormone found in the circulation is generally bound to GH-binding proteins. Binding to the cell surface receptor promotes receptor dimerization and phosphorylation and hence activation. This leads to the phosphorylation of various cystolic protein substrates, which mediate intracellular effects of the hormone...

Guinea who have SR levels 50% that of controls of normal stature the levels of GH, IGF-1, and low-affinity GH-binding protein levels are comparable in the two groups [25],... 

The presence of serum-binding proteins. Some biopharmaceuticals (including insulin-like growth factor (IGF), GH and certain cytokines) are notable in that the blood contains proteins that specifically bind them. Such binding proteins can function naturally as transporters or activators, and binding can affect characteristics such as serum elimination rates. 

GH deficiency often leads to delayed puberty. This condition often responds to exogenous GH administration. IGFs, as well as their receptors and binding proteins, are widespreadly expressed in the male and female reproductive tissue. Thus, IGFs are believed to affect reproductive function by both (GH-stimulated) endocrine action and via paracrine- and autocrine-based activity. 

A small number of children with growth failure have severe IGF-1 deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and development of neutralizing antibodies to GH. In 2005, the FDA approved mecasermin for treatment of severe IGF-1 deficiency that is not responsive to GH. Mecasermin is a complex of recombinant human IGF-1 (rhIGF-1) and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3). 

Mecasermin Recombinant form of IGF-1 that stimulates IGF-1 receptors Restores normal growth and metabolic IGF-1 effects in individuals with IGF-1 deficiency Replacement in IGF-1 deficiency that is not responsive to exogenous GH SC injection 2 x/d also contains recombinant human IGF-binding protein-3, which prolongs the half-life of the rIGF-1 Toxicity Hypoglycemia, intracranial hypertension, increased liver enzymes... 

Recombinant IGF-1 (genetically engineered) was reported to be effective when injected intramuscularly because it causes localized growth. This was the most popular method, and the agreed wisest for the most part. The drug has a half-life of about 10 minutes, and if it is or has been bound to IGF -BP-3, (INSULIN GROWTH FACTOR BINDING PROTEIN) the half- life is extended to about 12 hours. Pro s often stacked Insulin and/or GH with IGF-1 because IGF-1 shuts off natural GH production and GH causes Insulin resistance. IGF-1 is often referred to as Pro-insulin because it counteracts Insulin resistance and interacts with insulin. But this would actually be an untrue term for IGF-1. 

Figure 7.42. Model for regulation of AFP synthesis in winter flounder (Pleuronectes americanus). CNS central nervous system GHRH growth hormone releasing hormone GH growth hormone IGF-1 insulin-like growth factor-1 C/EBPa CCAAT enhancer binding protein a AEP antifreeze enhancerbinding protein. See text for details. Arrows with striped tails denote up-regulation or down-regulation.

GH may also stimulate production of at least some of the somatomedin-binding proteins. Production of binding proteins by hepatocytes in vitro has been demonstrated [60,61,64], as has its stimulation by GH. The 150K binding protein appears to be controlled by GH but not the 50K protein. 

The specific effects of GH on induction of somatomedin C (and its binding proteins) can be readily interpreted in terms of overall effects on somatic growth. The hormone also has effects on the production of other specific proteins, although here the connection with growth is less apparent. 

The WD repeat motif has first been identified in the subunit of the GTP-binding protein transducin and been referred to as transducin repeat, GH-WD repeat, or WD40 repeat. A single WD repeat comprises a peptide sequence of44-60 residues length. The canonical repeat ends with the W-D motif and possesses a G-H sequence about 11-24 residues from its N-terminus. This... 

One of the characteristic structure of all coronins are their central WD40 domains (see ref 9 and Chapters 2 and 5). These repeats are characterized by a -30-40 amino acid residue segment that are bordered by Gly-His (GH) andTrp-Asp (WD) peptide tesidues. " The WD repeat unit was first recognized in the beta subunit of the GTP binding protein transducin. This domain seems to have evolved with the eukaryotic kingdom and may be involved in protein protein interactions, although the precise function of the WD repeat domains in many proteins remains unknown. ... 

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