scholarly journals Specificity and promiscuity of gonadotropin receptors

Reproduction ◽  
2005 ◽  
Vol 130 (3) ◽  
pp. 275-281 ◽  
Author(s):  
Sabine Costagliola ◽  
Eneko Urizar ◽  
Fernando Mendive ◽  
Gilbert Vassart

The dichotomy between hormone recognition by the ectodomain and activation of the G protein by the rhodopsin-like serpentine portion is a well established property of glycoprotein hormone receptors. The specificity barrier avoiding promiscuous activation of the FSH receptor by the high concentration of human chorionic gonadotropin (hCG) prevailing during human pregnancy was thus believed to lie in the ectodomain. In the past two years, mutations responsible for rare spontaneous cases of ovarian hyperstimulation syndromes have partially modified this simple view. Five naturally occurring mutations have been identified which cause an increase in the sensitivity of the FSH receptor to hCG. Surprisingly, these mutations are all located in the serpentine portion of the receptor. In addition to their effect on sensitivity to hCG, they increase sensitivity of the FSH receptor to TSH, and are responsible for activating the receptor constitutively. Together, the available information indicates that the ectodomain and the serpentine domain of the FSH receptor each contribute to the specificity barrier preventing its spurious activation by hCG. While the former is responsible for establishment of binding specificity, the latter introduces a novel notion of functional specificity.Recent data demonstrate that LH and FSH receptors can constitute functional homo- and heterodimers. This suggests the possibility that in cells co-expressing the two receptors, such as granulosa cells, the heterodimers might be endowed with functional characteristics different from those of each homodimer.

Endocrinology ◽  
2000 ◽  
Vol 141 (11) ◽  
pp. 4081-4090 ◽  
Author(s):  
Shinya Nishi ◽  
Sheau Yu Hsu ◽  
Karen Zell ◽  
Aaron J. W. Hsueh

Abstract The receptors for lutropin (LH), FSH, and TSH belong to the large G protein-coupled receptor (GPCR) superfamily and are unique in having a large N-terminal extracellular (ecto-) domain important for interactions with the large glycoprotein hormone ligands. Recent studies indicated the evolution of a large family of the leucine-rich repeat-containing, G protein-coupled receptors (LGRs) with at least seven members in mammals. Based on the sequences of mammalian glycoprotein hormone receptors, we have identified a new LGR in Drosophila melanogaster and named it as fly LGR2 to distinguish it from the previously reported fly LH/FSH/TSH receptor (renamed as fly LGR1). Genomic analysis indicated the presence of 10 exons in fly LGR2 as compared with 16 exons in fly LGR1. The deduced fly LGR2 complementary DNA (cDNA) showed 43 and 64% similarity to the fly LGR1 in the ectodomain and transmembrane region, respectively. Comparison of 12 LGRs from diverse species indicated that these proteins can be divided into three subfamilies and fly LGR1 and LGR2 belong to different subfamilies. Potential signaling mechanisms were tested in human 293T cells overexpressing the fly receptors. Of interest, fly LGR1, but not LGR2, showed constitutive activity as reflected by elevated basal cAMP production in transfected cells. The basal activity of fly LGR1 was further augmented following point mutations of key residues in the intracellular loop 3 or transmembrane VI, similar to those found in patients with familial male precocious puberty. The present study reports the cloning of fly LGR2 and indicates that the G protein-coupling mechanism is conserved in fly LGR1 as compared with the mammalian glycoprotein hormone receptors. The characterization of fly receptors with features similar to mammalian glycoprotein hormone receptors allows a better understanding of the evolution of this unique group of GPCRs and future elucidation of their ligand signaling mechanisms.


2004 ◽  
Vol 18 (8) ◽  
pp. 2061-2073 ◽  
Author(s):  
Lucia Montanelli ◽  
Joost J. J. Van Durme ◽  
Guillaume Smits ◽  
Marco Bonomi ◽  
Patrice Rodien ◽  
...  

Abstract Recently, three naturally occurring mutations in the serpentine region of the FSH receptor (FSHr) (D567N and T449I/A) have been identified in three families with spontaneous ovarian hyperstimulation syndrome (OHSS). All mutant receptors displayed abnormally high sensitivity to human chorionic gonadotropin and, in addition, D567N and T449A displayed concomitant increase in sensitivity to TSH and detectable constitutive activity. In the present study, we have used a combination of site-directed mutagenesis experiments and molecular modeling to explore the mechanisms responsible for the phenotype of the three OHSS FSHr mutants. Our results suggest that all mutations lead to weakening of interhelical locks between transmembrane helix (TM)-VI and TM-III, or TM-VI and TM-VII, which contributes to maintaining the receptor in the inactive state. They also indicate that broadening of the functional specificity of the mutant FSHr constructs is correlated to their increase in constitutive activity. This relation between basal activity and functional specificity is a characteristic of the FSHr, which is not shared by the other glycoprotein hormone receptors. It leads to the interesting suggestion that different pathways have been followed during primate evolution to avoid promiscuous stimulation of the TSHr and FSHr by human chorionic gonadotropin. In the hFSHr, specificity would be exerted both by the ectodomain and the serpentine portion.


2020 ◽  
Vol 34 (8) ◽  
pp. 11243-11256
Author(s):  
Annelie Schulze ◽  
Gunnar Kleinau ◽  
Susanne Neumann ◽  
Patrick Scheerer ◽  
Torsten Schöneberg ◽  
...  

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