TY - JOUR
T1 - Preferential ligand selectivity of the monkey type-II gonadotropin- releasing hormone (GnRH) receptor for GnRH-2 and its analogs
AU - Wang, Ai Fen
AU - Li, Jian Hua
AU - Maiti, Kaushik
AU - Kim, Wang Phil
AU - Kang, Hae Mook
AU - Seong, Jae Young
AU - Kwon, Hyuk Bang
N1 - Funding Information:
This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare (01-PJ1-PG3-20500-0035) and a grant of the Korea Science and Engineering Foundation (KOSEF) through Hormone Research Center (HRC-2002-G0102).
PY - 2003/11/14
Y1 - 2003/11/14
N2 - Gonadotropin-releasing hormone (GnRH) regulates the reproductive system through the cognate GnRH receptor (GnRHR) in vertebrates. In this study, we cloned a cDNA encoding the full-length open reading frame sequence for green monkey type-II GnRHR (gmGnRHR-2) from the genomic DNA of CV-1 cells. Transient transfection study showed that gmGnRHR-2 was able to induce both c-fos promoter- and cAMP responsive element-driven transcriptional activities, indicating that gmGnRHR-2 couples to both Gs- and Gq/11-linked signaling pathways. gmGnRHR-2 responded better to GnRH-2 ([His5, Trp 7, Tyr8]GnRH) than GnRH-1 ([Tyr5, Leu 7, Arg8]GnRH). Substitutions of His5, Trp 7, and/or Tyr8 in GnRH-1 increased the potency to activate gmGnRHR-2, suggesting that individual His5, Trp 7, and Tyr8 in GnRH-2 contributed to differential ligand sensitivity of gmGnRHR-2. Substitution of D-Ala for Gly6 in GnRH-2 increased the potency to activate the receptor, suggesting that GnRH-2 has a constrained conformation when it binds to the receptor. GnRH-induced gmGnRHR-2 activation was specifically inhibited by GnRH-2 antagonists, Trptorelix-1 and -2, but not by a GnRH-1 antagonist, Cetrorelix. In conclusion, gmGnRHR-2 revealed preferential ligand selectivity for GnRH-2 and its analogs, suggesting that gmGnRHR-2 has a functional activity that is different from mammalian type-I GnRHRs but similar to non-mammalian GnRHRs.
AB - Gonadotropin-releasing hormone (GnRH) regulates the reproductive system through the cognate GnRH receptor (GnRHR) in vertebrates. In this study, we cloned a cDNA encoding the full-length open reading frame sequence for green monkey type-II GnRHR (gmGnRHR-2) from the genomic DNA of CV-1 cells. Transient transfection study showed that gmGnRHR-2 was able to induce both c-fos promoter- and cAMP responsive element-driven transcriptional activities, indicating that gmGnRHR-2 couples to both Gs- and Gq/11-linked signaling pathways. gmGnRHR-2 responded better to GnRH-2 ([His5, Trp 7, Tyr8]GnRH) than GnRH-1 ([Tyr5, Leu 7, Arg8]GnRH). Substitutions of His5, Trp 7, and/or Tyr8 in GnRH-1 increased the potency to activate gmGnRHR-2, suggesting that individual His5, Trp 7, and Tyr8 in GnRH-2 contributed to differential ligand sensitivity of gmGnRHR-2. Substitution of D-Ala for Gly6 in GnRH-2 increased the potency to activate the receptor, suggesting that GnRH-2 has a constrained conformation when it binds to the receptor. GnRH-induced gmGnRHR-2 activation was specifically inhibited by GnRH-2 antagonists, Trptorelix-1 and -2, but not by a GnRH-1 antagonist, Cetrorelix. In conclusion, gmGnRHR-2 revealed preferential ligand selectivity for GnRH-2 and its analogs, suggesting that gmGnRHR-2 has a functional activity that is different from mammalian type-I GnRHRs but similar to non-mammalian GnRHRs.
KW - GnRH analogs
KW - GnRH-2
KW - Ligand selectivity
KW - Monkey type-II GnRH receptor
UR - http://www.scopus.com/inward/record.url?scp=0242266467&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2003.08.004
DO - 10.1016/j.mce.2003.08.004
M3 - Article
C2 - 14604814
AN - SCOPUS:0242266467
SN - 0303-7207
VL - 209
SP - 33
EP - 42
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -