Disease relevance of GHR

• To obtain an animal model for studying the role of the GH receptor (GHR) in growth and development, we analyzed a sex-linked dwarf (SLD) chicken strain (Leghorn) which exhibits phenotype similarities with a human genetic growth disorder, an autosomal recessive GH resistance condition (Laron dwarfism) [1].
• Following an initial 2-week delay after hatching, there was a progressive increase in hepatic GHR mRNA which continued after the birds reached mature body weight [2].
• GH is not the sole regulator of GHR abundance, however; hypersomatropism induced by hypothyroidism was associated with an increase in GHR mRNA [3].

High impact information on GHR

• Sequencing of the whole coding region of the chicken GHR cDNA identified a G-to-T transversion segregating with the SLD phenotype and generating an isoleucine instead of a serine at position 199 within a highly conserved region close to the junction between the extracellular and transmembrane domains [1].
• Having previously demonstrated the responsibility of the human GHR gene in the Laron phenotype, we focused our analysis on the corresponding gene in SLD chickens [1].
• Transfection of a mutated GHR cDNA containing this mutation into eukaryotic cells led to the synthesis of a receptor protein that displayed impaired plasma membrane expression and binding activity [1].
• Chicken ghrelin mRNA is predominantly expressed in the stomach, where it is present in the proventriculus but absent in the gizzard [4].
• In addition, chicken ghrelin also increases plasma corticosterone levels in growing chicks at a lower dose than in mammals [4].

Biological context of GHR

• In contrast, intracerebroventricular (ICV) injection of ghrelin inhibits food intake in neonatal chicks [5].
• Genomic organisation of the chicken ghrelin gene and its single nucleotide polymorphisms detected by denaturing high-performance liquid chromatography [6].
• (2) Here, we report the complete sequence of chicken ghrelin gene (submitted to Genbank; accession number AY303688), which consists of 5 exons and 4 introns [6].
• Nucleotide sequence (CDS) predicted a 116 amino acid precursor protein (preproghrelin) for both the chicken and the turkey that demonstrated complete conservation of an N-terminal 'active core' (GSSF) including a serine (position 3 of the mature hormone) known to be a modification (acylation) site important for ghrelin bioactivity [7].
• (3) Scanning point mutations with denaturing high-performance liquid chromatography (DHPLC) using WAVE DNA Fragment Analysis Systems and confirmed with direct sequencing for polymerase chain reaction (PCR) products, we analysed the single nucleotide polymorphisms (SNPs) in the entire gene of chicken ghrelin [6].

Anatomical context of GHR

• The level of ghrelin mRNA increased in proventriculus in response to fasting but did not decline with subsequent refeeding [7].
• Ghrelin mRNA levels declined in broiler pancreas after a 48 h fast and increased upon refeeding [7].
• (1) Ghrelin is a novel endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and is expressed primarily in the stomach and hypothalamus with the probable function of stimulating GH secretion and food intake both in mammals and poultry [6].
• On the contrary, in extrahepatic tissues such as spleen, lung, brain, kidney, heart, intestine, thymus, and muscle, IGF-I mRNA expression was equally observed in normal and GHR-lacking dwarf chickens [8].
• Since GH- and GHR-like proteins are present in most tissues of the chick embryo, it is proposed that extrapituitary GH may act as a local growth factor during embryonic development [9].

Associations of GHR with chemical compounds

• In these SNPs, one mutation in exon 5 (A2355G) led to the change of amino acid from glutamine to arginine (Gln 113 Arg): as a result a different ghrelin precursor instead of a mature peptide was produced [6].
• Moreover, ghrelin 1-18 increased the expression of PCNA, cyclin, bax and p53 in cultures of ovarian follicular fragments, where it also stimulated the release of progesterone, estradiol, arginine-vasotocin (AVT) and IGF-I, but not of testosterone [10].
• Exogenous administration of octanoic acid accelerates octanoylated ghrelin production in the proventriculus of neonatal chicks [11].
• Chicken ghrelin and growth hormone-releasing peptide-2 inhibit food intake of neonatal chicks [12].
• Ghrelin increased T and decreased E(2,) but did not affect P(4) or AVT secretion [13].

Other interactions of GHR

• These results indicate that central ghrelin does not interact with NPY as seen in rodents, but instead inhibits food intake by interacting with the endogenous CRF and its receptor [5].
• Co-injection of a CRF receptor antagonist, astressin, attenuated ghrelin-induced plasma corticosterone increase and anorexia [5].
• Expression of the gene encoding the receptor for ghrelin (growth hormone secretagogue receptor, GHS-R) and a variant form was detected in a variety of tissues collected from 3-week-old male broiler chickens possibly suggesting autocrine/paracrine effects [7].
• In addition, one SNP in 5'UTR (C223G) determined the presence or absence of a potential binding site of transcription factor serum response factor (SRF), which might affect the expression of chicken ghrelin gene [6].
• The sex-linked dwarf (dwdw) chicken represents a valuable animal model for studying GH insensitivity and the consequence of mutations in the GH receptor (GHR) gene [14].

Analytical, diagnostic and therapeutic context of GHR

• RT-PCR was used to quantify ghrelin mRNA levels relative to 18S rRNA in 3-week-old male broiler chickens [7].
• Using molecular cloning techniques we have sequenced cDNAs corresponding to chicken (White Leghorn) and turkey ghrelin mRNAs [7].
• The study here was conducted using an immunohistochemistry assay to screen whether plants have any ghrelin immunoreactivity [15].
• Intraperitoneal or oral administration of OA for a few days significantly increased the density of ghrelin-ip cells without any changes in ghrelin-ex cells and elevated only octanoylated ghrelin levels in the proventriculus [11].
• In this study, we investigated ghrelin expression and distribution of ghrelin-producing cells in the hatching and adult chicken gastrointestinal tract by RT-PCR, immunohistochemistry and in situ hybridization [16].

References