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Inhibitory effects of antagonistic analogs of GHRH on GH3 pituitary cells overexpressing the human GHRH receptor

Authors
 M Kovacs  ;  AV Schally  ;  EJ Lee  ;  R Busto  ;  P Armatis  ;  K Groot  ;  JL Varga 
Citation
 JOURNAL OF ENDOCRINOLOGY, Vol.175(2) : 425-434, 2002 
Journal Title
 JOURNAL OF ENDOCRINOLOGY 
ISSN
 0022-0795 
Issue Date
2002
MeSH
Animals ; Cyclic AMP/analysis ; Cyclic AMP/biosynthesis ; Gene Expression/genetics ; Growth Hormone/analysis ; Growth Hormone/metabolism ; Growth Hormone-Releasing Hormone/analogs & derivatives* ; Growth Hormone-Releasing Hormone/antagonists & inhibitors ; Growth Hormone-Releasing Hormone/genetics ; Humans ; Pituitary Gland/cytology ; Pituitary Gland/physiology* ; Prolactin/analysis ; RNA, Messenger/genetics ; Rats ; Receptors, Somatotropin/genetics* ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured
Abstract
GH3 rat pituitary tumor cells produce GH and prolactin (PRL), but lack the GHRH receptor (GHRH-R). We expressed human GHRH-R (hGHRH-R) in GH3 cells using recombinant adenoviral vectors and studied the effects of GHRH antagonists. The mRNA expression of the GHRH-R gene in the cells was demonstrated by RT-PCR. An exposure of the GH3 cells infected with hGHRH-R to 10(-10), 10(-9) and 10(-8) m hGHRH for 1 or 2 h in culture caused a dose-dependent elevation of the intracellular cAMP concentration and the cAMP efflux. Exposure to hGHRH also elicited dose-dependent increases in GH and PRL secretion from these cells. Neither the uninfected nor the antisense hGHRH-R-infected control cells exhibited cAMP, GH and PRL responses to GHRH stimulation. GHRH antagonists JV-1-38 and jv-1-36 applied at 3x10(-8) m for 3 h, together with 10(-9) m GHRH, significantly inhibited the GHRH-stimulated cAMP efflux from the hGHRH-R-infected cells by 36 and 80% respectively. The more potent antagonist JV-1-36 also decreased the intracellular cAMP levels in these cells by 55%. Exposure to JV-1-36 for 1 h nullified the stimulatory effect of GHRH on GH secretion and significantly inhibited it by 64 and 77% after 2 and 3 h respectively. In a superfusion system, GHRH at 10(-10), 10(-9) and 10(-8) m concentrations induced prompt and dose-related high cAMP responses and smaller increases in the spontaneous GH secretion of the hGHRH-R-infected cells. Antagonists JV-1-36 and JV-1-38 applied at 3x10(-8) m for 15 min, together with 10(-9) m GHRH, inhibited the GHRH-stimulated cAMP response by 59 and 35% respectively. This work demonstrates that GHRH antagonists can effectively inhibit the actions of GHRH on the hGHRH-R. Our results support the view that this class of compounds would be active clinically.
Files in This Item:
T200205938.pdf Download
DOI
10.1677/joe.0.1750425
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/143927
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