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Growth Hormone‐Releasing Hormone: Discovery, Regulation, and Actions

Lawrence A. Frohman, Rhonda D. Kineman

10.1002/cphy.cp070508

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Historical Aspects
1.1 Biological Evidence for a Hypothalamic Growth Hormone–Releasing Factor
1.2 Purification
2 Anatomical Localization
2.1 Central Nervous System
2.2 Extracranial
2.3 Atypical
3 Molecular Biology and Chemistry of Hypothalamic Growth Hormone–Releasing Hormone
3.1 Gene Expression
3.2 Peptide Processing
4 Growth Hormone–Releasing Hormone Actions
4.1 Growth Hormone–Releasing Hormone Receptor
4.2 Signal‐Transduction Pathways
4.3 Regulation of Growth Hormone–Releasing Hormone Receptor Synthesis and Activity
4.4 Additional Actions
5 Regulation of Growth Hormone–Releasing Hormone Synthesis and Secretion
5.1 Hypothalamic Negative‐Feedback Effects of Growth Hormone
5.2 Glucocorticoids
5.3 Gonadal Steroids
5.4 Neurotransmitters
5.5 Signal‐Transduction Pathways which Lead to Growth Hormone–Releasing Hormone Release
5.6 Ontogenesis and Senescence of the Hormone‐Receptor System
5.7 Metabolic Changes
6 Future Directions
Figure 1. Figure 1.

Schematic representation of the growth hormone–releasing hormone (GHRH) gene, mRNA, and prohormone. Hypothalamic GHRH mRNA is derived from five exons, spanning a 10 kb region of the genome. In rodent placenta and testis, there is a unique transcription‐initiation site approximately 10 kb upstream of that used in the hypothalamus, resulting in a tissue‐specific first exon. Since the translation start site is located in the second exon, the peptide product in all tissues is identical. No evidence currently exists for corresponding upstream transcription‐initiation sites in humans. UT, untranslated.
Figure 2. Figure 2.

Posttranslational processing of the human growth hormone–releasing hormone (GHRH) prohormone. Only in humans is there evidence for further processing of the N‐terminally amidated hormone to a second, biologically active hormone.
Figure 3. Figure 3.

Comparative sequences of growth hormone–releasing hormone (GHRH). Areas in boxes indicate amino acid sequences differing from those in human GHRH.
Figure 4. Figure 4.

Model of the growth hormone–releasing hormone receptor. The receptor is a member of the secretin–vasoactive intestinal peptide family, consisting of seven transmembrane‐spanning regions and coupled to the Gs protein for signal transduction. The signal peptide cleavage site and the location of mutations in the lit/lit mouse and humans that are associated with loss of signal transduction and severe growth hormone deficiency (GHD) are indicated by arrows.
Figure 5. Figure 5.

Theoretical model of growth hormone–releasing hormone (GHRH) signal transduction in the somatotrope. The GHRH binds to a cell‐surface G protein–coupled receptor (R). Binding of the ligand to the receptor results in a conformational change which activates and releases the α subunit (Gs α) of the heterotrimeric G‐protein complex. Free Gs α stimulates the membrane‐bound enzyme adenylate cyclase (AC) to convert adenosine triphosphate (ATP) to 3′,5′ cyclic adenosine monophosphate (cAMP), which activates the catalytic subunit (c) of protein kinase A (PKA), which in turn translocates to the nucleus and phosphorylates cAMP‐response element–binding protein (CREB). Phosphorylated CREB binds to its respective response elements (CRE) within the promoter regions of the growth hormone (gh), pituitary transcription factor‐1 (pit‐1), growth hormone–releasing hormone receptor (ghrh‐r), and c‐fos genes to activate their transcription. Pit‐1 positively autoregulates its own transcription and augments expression of the gh and ghrh‐r genes. Also, PKA can result in the release of GH secretory vesicles by the phosphorylation of Na+ or nonselective monovalent cation channels, which results in depolarization of the plasma membrane and influx of extracellular Ca2+ into the cytoplasm. The rise in intracellular Ca2+ stimulates the release of GH and activates K+ channels, which reset plasma membrane polarity.


Figure 1.

Schematic representation of the growth hormone–releasing hormone (GHRH) gene, mRNA, and prohormone. Hypothalamic GHRH mRNA is derived from five exons, spanning a 10 kb region of the genome. In rodent placenta and testis, there is a unique transcription‐initiation site approximately 10 kb upstream of that used in the hypothalamus, resulting in a tissue‐specific first exon. Since the translation start site is located in the second exon, the peptide product in all tissues is identical. No evidence currently exists for corresponding upstream transcription‐initiation sites in humans. UT, untranslated.



Figure 2.

Posttranslational processing of the human growth hormone–releasing hormone (GHRH) prohormone. Only in humans is there evidence for further processing of the N‐terminally amidated hormone to a second, biologically active hormone.



Figure 3.

Comparative sequences of growth hormone–releasing hormone (GHRH). Areas in boxes indicate amino acid sequences differing from those in human GHRH.



Figure 4.

Model of the growth hormone–releasing hormone receptor. The receptor is a member of the secretin–vasoactive intestinal peptide family, consisting of seven transmembrane‐spanning regions and coupled to the Gs protein for signal transduction. The signal peptide cleavage site and the location of mutations in the lit/lit mouse and humans that are associated with loss of signal transduction and severe growth hormone deficiency (GHD) are indicated by arrows.



Figure 5.

Theoretical model of growth hormone–releasing hormone (GHRH) signal transduction in the somatotrope. The GHRH binds to a cell‐surface G protein–coupled receptor (R). Binding of the ligand to the receptor results in a conformational change which activates and releases the α subunit (Gs α) of the heterotrimeric G‐protein complex. Free Gs α stimulates the membrane‐bound enzyme adenylate cyclase (AC) to convert adenosine triphosphate (ATP) to 3′,5′ cyclic adenosine monophosphate (cAMP), which activates the catalytic subunit (c) of protein kinase A (PKA), which in turn translocates to the nucleus and phosphorylates cAMP‐response element–binding protein (CREB). Phosphorylated CREB binds to its respective response elements (CRE) within the promoter regions of the growth hormone (gh), pituitary transcription factor‐1 (pit‐1), growth hormone–releasing hormone receptor (ghrh‐r), and c‐fos genes to activate their transcription. Pit‐1 positively autoregulates its own transcription and augments expression of the gh and ghrh‐r genes. Also, PKA can result in the release of GH secretory vesicles by the phosphorylation of Na+ or nonselective monovalent cation channels, which results in depolarization of the plasma membrane and influx of extracellular Ca2+ into the cytoplasm. The rise in intracellular Ca2+ stimulates the release of GH and activates K+ channels, which reset plasma membrane polarity.

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Article Title: Growth Hormone‐Releasing Hormone: Discovery, Regulation, and Actions
 

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Lawrence A. Frohman, Rhonda D. Kineman. Growth Hormone‐Releasing Hormone: Discovery, Regulation, and Actions. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 187-219. First published in print 1999. doi: 10.1002/cphy.cp070508