Cellular mechanisms in the processing of growth hormone and its receptor

Roupas, Peter; Herington, Adrian C.

doi:10.1016/0303-7207(89)90184-6

Cited by 98 publications

(37 citation statements)

References 115 publications

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“…Also, two patients had received the highest dose of GHRH(1-29)NH 2 prior to the lower dose which could have had a priming effect, although the Latin-squares design of this study would have randomized for this and the time interval between studies makes such an effect unlikely in normal GH replete individuals. At a cellular level, the GHRH receptor is G-protein linked (26) and should not experience the inhibition seen at high ligand concentrations in vitro with receptors that require dimerization (27). There is no evidence that mobilization of stored GH pools is reduced by higher concentrations of GHRH and in vivo studies of cultured somatotropes have shown typical dose-response curves (26).…”

Section: Discussionmentioning

confidence: 99%

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Achermann

Brook

Hindmarsh

2000

European Journal of Endocrinology

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Objective: Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls. Design: Randomized controlled study. Methods: Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30 Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH 2 was administered in doses at the lower (0.05 mg/ kg) and upper (0.15 mg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1.0 mg/kg). GH was measured before stimulation, every 2 min for the first hour and every 5 min for the second hour. All studies were conducted in a random fashion. Results: Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 mg/kg (median peak Irradiated, 4.5 mU/l vs median Controls, 37.4 mU/l; P<0.01) and 1.0 mg/kg (median peak Irradiated, 4.8 mU/l vs median Controls, 15.2 mU/l; P<0.05) GHRH(1-29)NH 2 . In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH 2 (median AUC: 122 mU/l·min vs 179 mU/l·min vs 268 mU/l·min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness. Conclusion:The GH response to bolus GHRH(1-29)NH 2 is attenuated in adult long-term survivors of childhood brain tumours. This may reflect direct pituitary damage and/or the loss of the tropic effects of chronic GHRH deficiency.

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Section: Discussionmentioning

confidence: 99%

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Achermann

Brook

Hindmarsh

2000

European Journal of Endocrinology

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“…Although the adaptation of GH-receptor cycling to GH pulses applied less frequently than in vivo (e.g., two or four GH pulses per day) would not pose a problem under a ligand-driven receptor internalization model, hepatocytes may be unable to respond to GH pulses that recur more frequently than the endogenous male rhythm. Conceivably, in the seven-pulse-per-day experiments described in this report, the interpulse interval may be shorter than the minimum time needed for reappearance of unoccupied GH receptor at the cell surface, a process that probably requires new receptor-protein synthesis (38).…”

Section: Resultsmentioning

confidence: 99%

Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450.

Waxman

Pampori

Ram

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

224

177

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Plasma growth hormone (GH) profiles are sexually differentiated in many species and regulate the sexdependence of peripubescent growth rates and liver function, including steroid hydroxylase cytochrome P450 expression, by mechanisms that are poorly understood. By use of an external pump to deliver to hypophysectomized rats pulses of rat GH of varying frequency and amplitude, a critical element for liver discrimination between male and female GH patterns was identified. Liver expression of the male-specific steroid 2a(orl6a)-hydroxylase P450, designated CYP2C11, was stimulated by GH at both physiological and nonphysiological pulse amplitudes, durations, and frequencies, provided that an interpulse interval of no detectable GH was maintained for at least 2.5 hr. This rmding suggests that hepatocytes undergo an obligatory recovery period after stimulation by a GH pulse. This period may be required to reset a GH-activated intracellular signaling pathway or may relate to the short-term absence of GH receptors at the hepatocyte surface after a cycle of GH binding and receptor internalization. These requirements were distinguished from those necessary for the stimulation by GH of normal male growth rates in hypophysectomized rats, indicating that different GH responses and, perhaps, different GH-responsive tissues recognize distinct signaling elements in the sexually dimorphic patterns of circulating GH.Episodic secretion is a general characteristic of many hormones, including pituitary-dependent hormones, pancreatic islet, and parathyroid hormones (1), and is often crucial to the triggering of hormone-dependent responses in target cells. For growth hormone (GH), secretion by the pituitary is not only intermittent, or pulsatile, but also the frequency of pulsation is sex-dependent. In many species, including the rat, chicken, and human (2-5), pituitary GH secretion is more frequent in females than in males. In the case of the female rat, a high pulse frequency results in GH present in circulation continuously, at levels 2 10-20 ng/ml of plasma. This situation contrasts with the intermittent presence of GH in plasma of male rats (2, 6). Studies in rats (7-10) and mice (11-13) have demonstrated that the expression of a number of sexually differentiated hepatic proteins, including cytochrome P450 (P450)-linked steroid hydroxylases and drugmetabolizing enzymes, is primarily determined by plasma GH profiles and only secondarily regulated by the gonadal hormones through their effects on the hypothalamo-pituitary axis and its control of GH secretion (14-16).The plasma GH profile in a male rat is characterized by a pulse of 200-250 ng of GH per ml every 3-4 hr followed by a 2-to 2.5-hr period when circulating GH is nearly undetectable (.2 nrg/ml). It is unclear, however, just what features in this pattern are recognized as male by the hepatocyte. This critical question is addressed by the present study, which uses a recently developed external pump apparatus (17) for generation of periodic GH pulses of various frequenc...

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“…The sequence of events strongly suggests that the reduction in the number of surface receptors resulted from inhibition of translocation. The lag time between onset of inhibition of GHR translocation and surface GH binding is likely to reflect the time it takes the receptors to be removed from the cell surface by internalization, which occurs constitutively (26), and before the decrease in GH binding becomes detectable.…”

Section: Discussionmentioning

confidence: 99%

“…The GH binding assay with cell monolayers has been described previously (8). Briefly, recombinant human GH (9) was radiolabeled with Na 125 I (ARI, Sydney, Australia) by the Iodogen (Pierce) method to a specific activity of [20][21][22][23][24][25][26][27][28][29][30]. Monolayer cultures at a density of 4 ϫ 10 4 cells͞cm 2 were set up in 6-well plates (Flow Laboratories) and treated with insulin or IGF-I.…”

Section: Methodsmentioning

confidence: 99%

Insulin and insulin-like growth factor-I acutely inhibit surface translocation of growth hormone receptors in osteoblasts: A novel mechanism of growth hormone receptor regulation

Leung

Waters

Markus

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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We previously have demonstrated that insulin and insulin-like growth factor-I (IGF-I) down-regulate growth hormone (GH) binding in osteoblasts by reducing the number of surface GH receptors (GHRs). The present study was undertaken to investigate the mechanism of GHR downregulation. Treatment with 5 nM insulin or IGF-I for 18 hr significantly decreased surface GH binding to 26.4 ؎ 2.9% and 23.0 ؎ 2.7% of control (mean ؎ SE; P < 0.05), respectively. No corresponding reductions in the mRNA level and total cellular content of GHR were found, nor was the rate of receptor internalization affected. The effects on GHR translocation were assessed by measuring the reappearance of GH binding of whole cells after trypsinization to remove the surface receptors. GH binding of control cultures significantly increased (P < 0.05) over 2 hr after trypsinization, whereas no recovery of binding activity was detected in insulin and IGF-I-treated cultures, indicating that GHR translocation was impaired. Studies on the time course of GHR down-regulation revealed that surface GH binding was reduced significantly by 3-hr treatment (P < 0.0005), whereas GHR translocation was completely abolished by 75-90 min with insulin and IGF-I. The inhibition of receptor translocation by insulin, but not IGF-I, was attenuated by wortmannin. In conclusion, insulin and IGF-I down-regulated GH binding in osteoblasts by acutely impairing GHR translocation, with their effects exerted through distinct postreceptor signaling pathways.

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Cellular mechanisms in the processing of growth hormone and its receptor

Cited by 98 publications

References 115 publications

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450.

Insulin and insulin-like growth factor-I acutely inhibit surface translocation of growth hormone receptors in osteoblasts: A novel mechanism of growth hormone receptor regulation

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