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Endocrinology Vol. 138, No. 3 1058-1065
Copyright © 1997 by The Endocrine Society

Articles

Homologous Down-Regulation of Growth Hormone-Releasing Hormone Receptor Messenger Ribonucleic Acid Levels1

Grazia Aleppo, Stanley F. Moskal, II, Paula A. De Grandis, Rhonda D. Kineman and Lawrence A. Frohman

Department of Medicine, Section of Endocrinology and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Lawrence A. Frohman, M.D., Department of Medicine (M/C 787), University of Illinois at Chicago, 840 South Wood Street, Chicago, Illinois 60612.

Repeated stimulation of pituitary cell cultures with GH-releasing hormone (GHRH) results in diminished responsiveness, a phenomenon referred to as homologous desensitization. One component of GHRH-induced desensitization is a reduction in GHRH-binding sites, which is reflected by the decreased ability of GHRH to stimulate a rise in intracellular cAMP. In the present study, we sought to determine if homologous down-regulation of GHRH receptor number is due to a decrease in GHRH receptor synthesis. To this end, we developed and validated a quantitative RT-PCR assay system that was capable of assessing differences in GHRH-R messenger RNA (mRNA) levels in total RNA samples obtained from rat pituitary cell cultures. Treatment of pituitary cells with GHRH, for as little as 4 h, resulted in a dose-dependent decrease in GHRH-R mRNA levels. The maximum effect was observed with 0.1 and 1 nM GHRH, which reduced GHRH-R mRNA levels to 49 ± 4% (mean ± SEM) and 54 ± 11% of control values, respectively (n = three separate experiments; P < 0.05). Accompanying the decline in GHRH-R mRNA levels was a rise in GH release, reaching 320 ± 31% of control values (P < 0.01). Because of the possibility that the rise in medium GH level is the primary regulator of GHRH-R mRNA, we pretreated pituitary cultures for 4 h with GH to achieve a concentration comparable with that induced by a maximal stimulation with GHRH (8 µg GH/ml medium). Following pretreatment, cultures were stimulated for 15 min with GHRH and intracellular cAMP accumulation was measured by RIA. GH pretreatment did not impair the ability of GHRH to induce a rise in cAMP concentrations. However, as anticipated, GHRH pretreatment (10 nM) significantly reduced subsequent GHRH-stimulated cAMP to 46% of untreated controls. These data suggest that GHRH, but not GH, directly reduces GHRH-R mRNA levels. To determine whether this effect was mediated through cAMP, cultures were treated with forskolin, a direct stimulator of adenylate cyclase. Forskolin (10 µM) significantly reduced GHRH-R mRNA concentrations (37 ± 6% of control values) indicating that GHRH acts through the cAMP-second messenger system cascade to regulate GHRH-R mRNA. The somatostatin analogue, octreotide (10 nM), which has been previously reported to decrease adenylate cyclase activity, did not affect GHRH-R mRNA levels. Taken together, these results indicate that GHRH inhibits the production of its own receptor by a receptor-mediated, cAMP-dependent reduction of GHRH-R mRNA accumulation.




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