(written by LakeMountD)
Here is a clipping from a book I have been reading called 'Molecular Cell Biology', and I happened put some of it online. I found this extremely interesting, however. Although the exact half life of LR3 IGF-1 is not known, although estimates of 8-36 hours are what people have been saying (very big range). It is hard to say, however, after reading the following passage you will begin to see the reason that LR3 IGF-1 could only be lasting 3-4 weeks in most people. EGF is used as an example but most growth factors
activate the tyrosine kinanse receptor, which involves phosphorylation to accomplish activation. This phosphorylation causes the cytoplasmic end of the receptor (the part inside the cell) to open up and allow gene transcription in the cell to take place. However, once this occurs it takes time for the receptor to "recover", therefore, the constant administration of growth factors, especially growth factors with half lives as long as LR3 IGF-1, can cause degradation of the receptor and continually do so to multiple receptors, eventually (usually after 3-4 weeks) reducing the receptor count enough to see diminished gains. One might speculate that it would happen faster than this, however, IGF-1 also has a binding affinity (although not extremely high) for the insulin receptor, so it isn't only the IGF-1R that is affected. This "appears" to be the reason why we see diminished gains, based off of the literature I am reading. We basically need to allow these receptors to recover, which is probably around 12-24 hours for all tyrosine kinases, and it would appear that the active life or LR3 IGF-1 is roughly 24, although this isn't definite. Hence, it would also appear that the best route to take would be an EOD injection or POSSIBLY E3D injection scheme.
Here is an idea of what the receptor looks like and it also shows the cytoplasmic tail end of the receptor and how it works.
(excerpt from e-book)
Receptors for Many Peptide Hormones Are Down-Regulated by Endocytosis
The principal mechanism for down-regulating the receptors for many peptide hormones (e.g., insulin, glucagon, EGF, and PDGF) is ligand-dependent receptor-mediated endocytosis. In the absence of EGF ligand, for instance, the EGF receptor is internalized with bulk membrane flow. Binding to EGF induces a conformational change in the cytoplasmic tail of the receptor. This exposes a sorting motif that facilitates receptor recruitment into coated pits and subsequent internalization. After the receptor-hormone complex is internalized, the hormone is degraded in lysosomes a fate similar to that of other endocytosed proteins, such as low-density lipoproteins (see Figure 17-64). Unlike the low-density lipoprotein (LDL) receptor, internalized receptors for many peptide hormones do not recycle efficiently to the cell surface.
In the presence of EGF, for instance, the average half-life of an EGF receptor on a fibroblast cell is about 30 minutes; during its lifetime, each receptor mediates the binding, internalization, and degradation of only two EGF molecules. Each time an EGF receptor is internalized with bound EGF, it has a high probability (about 50 percent) of being degraded in an endosome or lysosome. Exposure of a fibroblast cell to high levels of EGF for 1 hour induces several rounds of endocytosis, resulting in degradation of most receptor molecules. If the concentration of extracellular EGF is then reduced, the number of EGF receptors on the cell surface recovers, but only after 12 24 hours. Synthesis of new receptors is needed to replace those degraded by endocytosis, which is a slow process that may take more than a day.
The fewer hormone receptors present on the surface of a cell, the less sensitive the cell is to the hormone; as a consequence, a higher hormone concentration is necessary to induce the usual physiological response. A simple numerical example illustrates this important point. Suppose a cell has 10,000 insulin receptors on its surface with a KD of 108 M. As noted earlier, in many cases only a fraction of the available receptors must bind ligand to induce the maximal physiological response (see Figure 20-7). If we assume only 1000 receptors must bind insulin to induce a physiological response (e.g., activation of glucose transport), we can calculate the insulin concentration [H] needed to induce this response from Equation (20-2) rewritten in the following form:
where RT = 10,000 (the total number of insulin receptors), KD = 108 M, and [RH] = 1000 (the number of insulinoccupied receptors). In this example, the necessary insulin concentrations is 1.1×109 M. If RT is reduced to 2000/cell, then a ninefold higher insulin concentration (108 M) is required to occupy 1000 receptors and induce the physiological response. If RT is further reduced to 1200/cell, an insulin concentration of 5 × 108 M, a 50-fold increase, is necessary to generate a response.
Experiments with mutant cell lines demonstrate that internalization of receptor tyrosine kinases plays an important role in regulating cellular responses to EGF and other growth factors. For instance, a mutation in the EGF receptor that makes it resistant to ligand-induced endocytosis or, in dynamin, that blocks formation of clathrin-coated endocytic vesicles substantially increases the sensitivity of cells to EGF as a mitogenic signal. Such mutant cells are prone to EGF- induced cell transformation. Interestingly, the mutant-dynamin inhibition of internalization also causes a qualitatively different pattern of phosphorylation of substrate proteins by the activated EGF receptor, as well as quantitative changes in the phosphorylation of known components in the EGF signaling pathways. Interestingly, internalized receptors can continue to signal from intracellular compartments prior to their degradation. This raises the intriguing possibility that receptor activity can be spatially controlled. Hence, internalization may modulate both the nature of RTK-transmitted signals, their magnitude, and location.
Studies with RTKs that bind PDGF suggest that PI-3 kinase plays an important role in the endocytosis and down-regulation of this class of receptors. Mutations that abolish the ability of the PDGF receptor to bind PI-3 kinase but not other enzymes (e.g., PLCg) cause a reduction in the rate of receptor degradation. Although the mutant receptor is internalized, its sorting to the lysosome for degradation is blocked by an unknown mechanism. The observation that yeast cells expressing a mutant PI-3 kinase exhibit defective sorting of proteins to the vacuole (the yeast lysosome) raises the intriguing possibility that this enzyme plays an important role in membrane trafficking both in yeasts and mammalian cells.
