Growth Hormone Secretagogue Binding Sites in Peripheral Human Tissues1

Abstract

The family of GH secretagogues (GHS) includes peptidyl (hexarelin) and nonpeptidyl (MK 0677) molecules possessing specific receptors in the brain, pituitary, and thyroid. GHS receptor subtypes have also been identified in the heart; and a gastric-derived peptide, named ghrelin, has recently been proposed as a natural ligand. Our aim was to investigate the presence of GHS receptors in a wide range of human tissues, by radioreceptor assay with [125 I]Tyr-Ala-hexarelin. GHS receptors were detected mainly in the myocardium, but they were also present (in order of decreasing binding activity) in adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid, adipose tissue, veins, uterus, skin, and lymphnode. In contrast, negligible binding was found in parathyroid, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon, and spleen. Hexarelin, MK 0677, and human ghrelin completely displaced the radioligand from binding sites of endocrine tissues, but MK 0677 and ghrelin were less potent than hexarelin. In nonendocrine tissues, both MK 0677 and ghrelin were inactive in displacement of [125 I]Tyr-Alahexarelin, whereas hexarelin was as active as a displacing agent in endocrine tissues. This study provides the first detailed analysis of the tissue localization of GHS receptors and suggests that a still unknown receptor subtype, specific for peptidyl GHS, may exist in the heart and in other tissues. (J Clin Endocrinol Metab 85: 3803-3807, 2000) G H SECRETAGOGUES (GHS) are synthetic, peptidyl [GH-releasing peptides (GHRPs)], and nonpeptidyl molecules that possess strong, dose-dependent, and reproducible GH-releasing activity in vivo in several species and in man. They are active by the iv, sc, intranasal route and even after oral administration (1-3). Both peptidyl and nonpeptidyl compounds also possess significant PRL-and ACTH/cortisol-releasing effect (4, 5). The neuroendocrine activities of GHRPs are mediated by specific receptors, which have originally been identified in the pituitary and the hypothalamus in humans (6), as well as in rats (7, 8), using radiolabeled peptidyl ([ 125 I]Tyr-Ala-hexarelin) or radiolabeled nonpeptidyl GHS ([ 35 S]MK 0677). A specific animal and human GHS receptor has recently been cloned (9). It is encoded by a rare messenger RNA (mRNA) with a predicted open reading frame of 366 amino acids with a transmembrane topology typified by the Gprotein-coupled receptor family. Receptor transcripts are expressed in the pituitary and the hypothalamus (4, 9), and their sequence shows partial homology with the neurotensin receptor and other orphan receptors, such as GPR38, GPR39, and FM-3 (10, 11).The hypothalamus and the pituitary gland display the highest specific GHS binding in humans and in animals (6 -9), though a high level of specific binding has also been found in other areas of the central nervous system, such as the cerebral (but not cerebellar) cortex, hippocampus, medulla oblongata, choroid plexuses, thalamus, striatum, and substantia nigr...

Growth Hormone Secretagogue (Ghrelin-) Receptors - A Complex Drug Target for the Regulation of Body Weight

“…The presence of GHS-R1a mRNA has been demonstrated specifically in heart and aorta. Both ligand and receptor were found in the myocardium and both ghrelin and peptidyl GHS recognize high affinity binding sites in the heart [45,46]. However it is important to mention that the expression of the GHS-R was only detected by RT-PCR, suggesting that GHS-R is only present at low levels in cardiac tissue.…”

“…In summary, the current opinion still is that the positive influence of GHS on cardiac functions is probably mediated by GHS-R1a. Supportive for this hypothesis are the findings that both ghrelin and GHSs recognize high affinity binding sites in the heart [45]. However, in a separate study, Baldanzi et al [50] demonstrated that the receptor mediating ghrelin actions in cardiomyocytes is not the GHS-R 1a, since this receptor was not localized in cardiomyocytes and both forms of ghrelin (acylated and nonacyl ghrelin, which does not bind to GHS-R 1a) were able to recognize a common binding site.…”

Circulating acylghrelin levels are suppressed by insulin and increase in response to hypoglycemia in healthy adult volunteers

“…Data regarding the regulation and action of UAG are less consistent (5). The ghrelin receptor is also located in peripheral tissues, indicating direct effects of AG (6). Among these effects, glucoregulatory properties seem to be important (5) and ghrelin-deficient mice developed profound hypoglycemia during calorie restriction (7).…”

Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor

“…Accordingly, ghrelin more closely mimics MK-0677, and it was assumed that the GHSR is the ghrelin receptor. However, evidence has been presented to suggest the existence of receptor subtypes (15). Furthermore, as a 28-aa peptide containing a unique octanoyl modification (11), ghrelin is structurally different from MK-0677.…”