Signaling by the luteinizing hormone/choriogonadotropin receptor (LHR) is of considerable interest because of its requirement for successful reproduction. Time-resolved phosphorescence anisotropy and fluorescence resonance energy transfer were used to investigate the organization of endogenous LHRs in porcine follicular membranes in two distinct signaling states, active and desensitized. Desensitized LHRs exhibited ϳ3-fold slower rotational correlation times compared with active LHRs (59 ؎ 4 and 21 ؎ 9 s, respectively), suggesting that with agonist-dependent desensitization the receptors are organized into larger protein complexes. Incubation of membranes with inhibitors of LHR desensitization, such as neutralizing anti-arrestin antibodies, a synthetic peptide corresponding to the third intracellular loop of the LHR but not the corresponding scrambled peptide, or catalytically inactive ARNO, resulted in faster rotational diffusion times equivalent to those of actively signaling LHRs. Furthermore, desensitized LHRs exhibited a 2.4-fold increase in fluorescence resonance energy transfer between LHRs suggesting that the larger protein aggregates formed during desensitization contain more self-associated LHRs. These results indicate that agonist-dependent LHR desensitization precedes organization of LHRs at the cells surface into larger protein aggregates. The luteinizing hormone/choriogonadotropin receptor (LHR)1 is a seven transmembrane-spanning receptor coupled to G-proteins, most typically the stimulatory guanine nucleotide-binding proteins, which activate adenylyl cyclase to produce the second messenger signal, cAMP (1). Mechanisms involved in signal transduction by the LHR are of considerable interest because of the importance of the receptors in mammalian reproduction. In females, activation of the LHR regulates terminal follicular development and promotes ovulation and during pregnancy maintains progesterone production by the corpus luteum (2). In males, LHR signaling promotes testosterone production by Leydig cells (2). Signal transduction by the LHR to G s can be tempered or desensitized as a consequence of arrestin2 (-arrestin1) binding to the receptor at the third intracellular (3i) loop (3). LHR desensitization occurs in ovarian follicles in response to the mid-cycle LH surge that promotes ovulation (4) and, based on serum progesterone levels, appears to occur in human corpora lutea in response to elevated levels of hCG during pregnancy (5).The  2 -adrenergic receptor has served as a model for desensitization of G-protein-coupled receptors (GPCRs). Following agonist activation, desensitization of the  2 -adrenergic receptor is triggered by receptor phosphorylation catalyzed by a G-protein receptor kinase (6, 7). The G-protein receptor kinase phosphorylation sites on the  2 -adrenergic receptor facilitate interaction of the receptor with non-visual arrestins (8). Arrestins sterically hinder the ability of the receptor to activate G-proteins and thus moderate signal transduction by GPCRs (9, 10). Howe...
SummarySeveral naturally-occurring mutations in human luteinizing hormone receptors (LHR) at position 578 are associated with constitutive activation of the receptor. To determine whether human LHRs that signal in the absence of ligand are self-associated, fluorescence resonance energy transfer (FRET) between receptors was evaluated. Values for FRET between wild type LHR in the absence of ligand were less than 1% and increased significantly to over 11% after exposure to hCG. Constitutively active receptors exhibited 11-15% FRET efficiency in the absence of hormone and these values did not change with hCG treatment. A large fraction of constitutively active LHR-D578H receptors were also associated with so-called plasma membrane rafts. Disruption of these membrane microdomains reduced FRET efficiency but did not affect signaling through cAMP. Thus, in the absence of ligand, constitutively-active receptors are self-associated and located in high buoyancy membrane fractions, both characteristics of the hormone-treated wild type receptor.
Signal transduction by luteinizing hormone receptors (LHRs) and follicle-stimulating hormone receptors (FSHRs) is essential for the successful reproduction of human beings. Both receptors and the thyroid-stimulating hormone receptor are members of a subset of G-protein coupled receptors (GPCRs) described as the glycoprotein hormone receptors. Their ligands, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and a structurally related hormone produced in pregnancy, human chorionic gonadotropin (hCG), are large protein hormones that are extensively glycosylated. Although the primary physiologic functions of these receptors are in ovarian function and maintenance of pregnancy in human females and spermatogenesis in males, there are reports of LHRs or FSHRs involvement in disease processes both in the reproductive system and elsewhere. In this review, we evaluate the aggregation state of the structure of actively signaling LHRs or FSHRs, their functions in reproduction as well as summarizing disease processes related to receptor mutations affecting receptor function or expression in reproductive and non-reproductive tissues. We will also present novel strategies for either increasing or reducing the activity of LHRs signaling. Such approaches to modify signaling by glycoprotein receptors may prove advantageous in treating diseases relating to LHRs or FSHRs function in addition to furthering the identification of new strategies for modulating GPCR signaling.
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