GH acts through a cell surface receptor, GHR, which is a member of the type 1 cytokine receptor family. Cytokine receptors have a single trans-membrane domain and dimerisation is required to activate intra-cellular signalling pathways. In common with other cytokine receptors the extra-cellular domain of the GHR is proteolitically cleaved and circulates as a binding protein. Under physiological conditions GH is in part bound in the circulation and the complex with the binding protein is presumed to be biologically inactive and protected from clearance and degradation. Co-administration of binding protein with GH in vivo delays GH clearance and augments its anabolic actions. Thus, like many hormonal systems, binding in the circulation provides an inactive circulating reservoir in equilibrium with free active hormones. Free GH is available to bind the cell surface GHR in a 1:2 complex. We have recently generated a fusion of GH with its extra-cellular domain GHR. In bioassays this ligand receptor fusion proved to be an agonist although with 25 fold less activity compared to native GH. However in vivo, in hypophysectomised rats, this ligand receptor fusion had 300 fold reduced clearance and proved to be a potent agonist. In conclusion, GHBP provides a natural reservoir of inactive hormone and fusion of GH to GHBP provides a very long-acting potent GH agonist.
03 - 07 May 2008
European Society of Endocrinology