Part of “CHAPTER 12 – GROWTH HORMONE AND ITS DISORDERS“

The GH receptor (GHR) is a 620-amino-acid, ˜130 kDa, single-chain glycoprotein with a single transmembrane domain, a large extracellular domain containing the GH-binding site, and an intracellular domain involved in GH signaling (Fig. 12-4).5 The extracellular domain also occurs separately as a soluble GH-binding protein (GHBP, see later). The GHR is a member of the cytokine receptor family that also includes the receptors for prolactin, erythropoietin and other hematopoietic growth factors, many of the interleukins, and others.6 The GHR is encoded by a single gene located on the short arm of chromosome 5. The gene spans at least 87 kb and is divided into 10 exons and 9 introns.7 Exons 2–7 encode the extracellular domain, exon 8 the trans-membrane domain, and exons 9 and 10 the intracellular domain. The GHR is expressed ubiquitously, with the liver being the organ most enriched in GHRs. In addition to the full-length GHR, two variants of the GHR are found in humans. A version lacking the 22 amino acids encoded by exon 3 is differentially expressed among tissues8 and/or in different individuals.9 This internal deletion near the amino terminus has no known functional consequence. The second variant is a GHR truncated at nine amino acids beyond the transmembrane domain, so that it lacks most of the intracellular domain.10 This variant is also expressed ubiquitously. The absence of an intracellular domain renders this variant incapable of signaling and favors prolonged persistence on the cell membrane. The latter may be the reason why this receptor variant contributes substantially to GHBP generation (see later). This truncated GHR variant modulates GH action by forming heterodimers with full-length GHRs, thereby sequestering some of the GHRs in a nonfunctional state.