J Korean Soc Endocrinol.  2006 Jun;21(3):173-183. 10.3803/jkes.2006.21.3.173.

Current Research on the Structure and Function of the Growth Hormone Releasing Hormone Receptor

• Gaylinn B

• KMID: 2200728
• DOI: http://doi.org/10.3803/jkes.2006.21.3.173

Abstract

Growth hormone releasing hormone receptor (GHRH-R) is a family B1 G-protein coupled receptor found predominantly on pituitary somatotrophs. In the adults it is required for the normal synthesis and release of growth hormone (GH) from the pituitary. During development it is required for the normal proliferation and maturation of somatotrophs within the pituitary. Mutations of this receptor in mouse and man are associated with GH deficiency, short stature and pituitary hypoplasia. This signaling system plays important roles in growth and development, metabolism of muscle and fat, and is implicated in the regulation of cardiac and immune function, wound healing, tumor growth and the aging process. Current areas of active research discussed here include: studiesof the structure of the receptor binding site and its interaction with GHRH, alternative splice variants of the GHRH-R which appear to promote tumor proliferation, truncated receptor isoforms that act as dominant negative inhibitors of wild type receptor, and the unclear physiologic role of the GHRH system in birds and fishes.

MeSH Terms

Adult
Aging
Animals
Binding Sites
Birds
Fishes
Growth and Development
Growth Hormone*
Growth Hormone-Releasing Hormone*
GTP-Binding Proteins
Humans
Metabolism
Mice
Protein Isoforms
Somatotrophs
Wound Healing
GTP-Binding Proteins
Growth Hormone
Growth Hormone-Releasing Hormone
Protein Isoforms

Figure

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  Fig. 1. Phylogenetic distance tree derived from computer alignment of amino acid sequences of human family B1 hormone receptors. Branch points represent statistically chosen hypothetical common ancestral sequences. Branch lengths are proportional to the number of amino acid changes from that hypothetical sequence. Scale bar indicates 0.1 changes per amino acid. PAC1-R, PACAP specific receptor; VPAC1-R, PACAP/VIP receptor type 1; VPAC2-R, PACAP /VIP receptor type 2.

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  Fig. 2. Cartoon model of GHRH-R structure showing sites of photoaffinity cross-linking. With GHRH bound to wild type receptor, cross-linkers at GHRH position 12 lie in close proximity to the stippled region, while linkers at GHRH positions 1 and 21 are close to different sites in the gray region. The single N-linked extracellular glycosylation site is shown at N. D indicates the site of a D to G point mutation (Asp60-Gly) that disrupts ligand binding in the lit mutant.

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  Fig. 3. Sites of mutations reported to affect GHRH-R function. P1 to P9 are the sites of reported receptor point mutations resulting in single amino acid substitutions. T1 to T8 are sites of reported truncations. T1- Truncation found in a Brazilian kindred with over 105 effected individuals.

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  Fig. 4. Cartoon illustrated the GHRH-R truncations mutants found to have dominant negative activity.

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  Fig. 5. cAMP signaling from the wild-type receptor is inhibited in proportion to the amount of the truncation mutant expressed.

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  Fig. 6. Sensitivity for GHRH activation of cAMP signaling is increased ten fold when the human GHRH-R is truncated by 16 amino acids.

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  Fig. 7. Illustration of GHRH-R splice variants SV-1, SV-2, SV-3 and SV-4. Regions encoded by intronic sequence not part of the pituitary receptor are shown striped, black regions are shared with the pituitary receptor; grey shows the signal peptide of the pituitary receptor.

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  Fig. 8. cAMP activation by human or chicken GHRH at HEK293 cells with and without transfection with chicken GHRH receptor.

Reference

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