To date, the GHS-R has been localized at the mRNA level by a combination of in situ hybridization, RNase protection and RT-PCR techniques. These strategies were required due to the extreme low abundance of GHS-R transcripts which prevented the use of Northern blotting analysis. The accumulated expression data suggests that the GHS-R gene is actively transcribed in the anterior pituitary gland and the brain, two known sites of GHS action. It will be of considerable interest to map the tissue distribution of GHS-R expression using antibody probes when these become available. Several reports have appeared detailing the expression pattern of the GHS-R by in situ hybridization. Collectively these results show that the GHS-R is expressed in the brain, present in both hypothalamic and non-hypothalamic regions.
Initial results were obtained in the rhesus monkey using non-overlapping radiolabeled oligonucleotide hybridization probes, which showed specific labehng of the arcuate-ventromedial hypothalamus and infindibular hypothalamus. The cloning of the rat GHS-R facilitated detailed mapping studies in the rat brain, again using radiolabeled oligonucleotides or full-length riboprobes. Both studies show that the GHS-R is prominently expressed in several hypothalamic nuclei, including the arcuate nucleus, the ventromedial hypothalamic, and supraoptic nucleus. Both the arcuate and ventromedial hypothalamic nuclei are thought to play a key role in the regulation of GH secretion. Significant hybridization signals were also noted in the dentate gyrus and CA2 layers of the hippocampus, a brain region which has not been strongly impUcated in growth control but is often associated with memory and learning. Attempts to finely determine the precise localization of the GHS-R within the hypothalamus in comparison to other neuronal markers has revealed that the GHS-R is localized to a region of the arcuate nucleus and ventromedial nucleus distinct from GHRH and NPY containing domains . Additionally, in the same study, GHS-R expression was markedly regulated by GH. In the GHdeficient dw/dw rat, GHS-R expression was increased while in dw/dw rats treated with GH, GHS-R expression decreased. These observations are in accord with the notion that GH regulates its own release through negative feedback loops in the hypothalamus involving GH, and in addition, GHS-Rs.
A recent study also attempted to identify the cell type in the arcuate and ventromedial hypothalamus which expresses the GHS-R. Using dual chromogenic and in situ hybridization, the GHS-R was found to co-localize to both arcuate and ventromedial hypothalamic cells which express GHRH. This results provides evidence that GHRH release into hypophyseal portal blood may be regulated by GHSs. RNase protection and RT-PCR analysis of GHS-R expression in normal tissues are generally consistent with expression confined to brain and pituitary gland. Three recent reports show by RT-PCR that transcripts for the GHS-R can be found in a variety of human tumors of pituitary origin including, somatotrophinomas, the rat pituitary cell Une GH3 and corticotrope adenoma (Cushing's disease).
This result confirms the presence of GHS-R in corticotrope adenomas and provides an explanation why GHRPs stimulate the release of ACTH in patients with Cushing's syndrome. The presence of the GHS-R transcripts in non-pituitary tumors (bronchial carcinoid) and in the renal pelvis is not firmly established at this time. The expression of the GHS-R in the brain suggests broader functions, beyond the control of GH release, for the GHS-R and its natural way in normal physiology.
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