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GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol.

ABSTRACT: Rapid, nongenomic actions of 17beta-oestradiol (E(2)) on hypothalamic neurones that may be relevant to reproductive function were described decades ago. The orphan G protein-coupled receptor, GPR30, was recently shown to bind oestrogens and to trigger rapid signalling in vitro, and is expressed in several rat and human brain regions, including the hypothalamus. We used two complementary approaches to investigate the role of GPR30 in hypothalamic responses to E(2) that are relevant to reproductive physiology. Serial blood sampling after the acute administration of the selective GPR30 agonist G1 was used to assess the role of GPR30 in short latency negative-feedback inhibition of luteinising hormone (LH) secretion and facilitation of prolactin secretion in ovariohysterectomised female rats. In vivo RNA interference (RNAi), mediated by adeno-associated virus-expressing small hairpin RNA (shRNA) infused into the mediobasal hypothalamus, was used to study the effects of GPR30 knockdown on these rapid responses to E(2). Longer-term actions of E(2) on female sexual behaviour (lordosis) were also examined in female rats subjected to in vivo RNAi. Administration of E(2) or G1 triggered a short latency surge of prolactin secretion, and animals subjected to GPR30 RNAi showed significantly less E(2)-dependent prolactin release than animals receiving control virus. G1 did not mimic E(2) negative-feedback inhibition of LH secretion, and GPR30 RNAi did not interfere with E(2) suppression of LH or facilitation of lordosis behaviour. These findings suggest that activation of GPR30 promotes short latency prolactin secretion but does not mediate E(2) negative-feedback inhibition of LH secretion or E(2) facilitation of female reproductive behaviour.

SUBMITTER: Lebesgue D

PROVIDER: S-EPMC2756443 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol.

Lebesgue D D Reyna-Neyra A A Huang X X Etgen A M AM

Journal of neuroendocrinology 20090612 9

Rapid, nongenomic actions of 17beta-oestradiol (E(2)) on hypothalamic neurones that may be relevant to reproductive function were described decades ago. The orphan G protein-coupled receptor, GPR30, was recently shown to bind oestrogens and to trigger rapid signalling in vitro, and is expressed in several rat and human brain regions, including the hypothalamus. We used two complementary approaches to investigate the role of GPR30 in hypothalamic responses to E(2) that are relevant to reproductiv ...[more]

PMID: 19523168

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Project description:BackgroundLuteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa.ObjectiveTo compare BMD change in men receiving either LHRHa or oestradiol patches (OP).Design, setting, and participantsMen with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr.InterventionsLHRHa as per local practice, OP (FemSeven 100μg/24h patches).Outcome measurements and statistical analysisThe primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance.Results and limitationsA total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001).ConclusionsTransdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial.Patient summaryThis study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial.Trial registrationISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Project description:UnlabelledThe ability of human cytomegalovirus (HCMV) to establish lifelong persistence and reactivate from latency is critical to its success as a pathogen. Here we describe a short-term in vitro model representing the events surrounding HCMV latency and reactivation in circulating peripheral blood monocytes that was developed in order to study the immunological consequence of latent virus carriage. Infection of human CD14(+) monocytes by HCMV resulted in the immediate establishment of latency, as evidenced by the absence of particular lytic gene expression, the transcription of latency-associated mRNAs, and the maintenance of viral genomes. Latent HCMV induced cellular differentiation to a macrophage lineage, causing production of selective proinflammatory cytokines and myeloid-cell chemoattractants that most likely play a role in virus dissemination in the host. Analysis of global cellular gene expression revealed activation of innate immune responses and the modulation of protein and lipid synthesis to accommodate latent HCMV infection. Remarkably, monocytes harboring latent virus exhibited selective responses to secondary stimuli known to induce an antiviral state. Furthermore, when challenged with type I and II interferon, latently infected cells demonstrated a blockade of signaling at the level of STAT1 phosphorylation. The data demonstrate that HCMV reprograms specific cellular pathways in monocytes, most notably innate immune responses, which may play a role in the establishment of, maintenance of, and reactivation from latency. The modulation of innate immune responses is likely a viral evasion strategy contributing to viral dissemination and pathogenesis in the host.ImportanceHCMV has the ability to establish a lifelong infection within the host, a phenomenon termed latency. We have established a short-term model system in human peripheral blood monocytes to study the immunological relevance of latent virus carriage. Infection of CD14(+) monocytes by HCMV results in the generation of latency-specific transcripts, maintenance of viral genomes, and the capacity to reenter the lytic cycle. During short-term latency in monocytes the virus initiates a program of differentiation to inflammatory macrophages that coincides with the modulation of cytokine secretion and specific cellular processes. HCMV-infected monocytes are hindered in their capacity to exert normal immunoprotective mechanisms. Additionally, latent virus disrupts type I and II interferon signaling at the level of STAT1 phosphorylation. This in vitro model system can significantly contribute to our understanding of the molecular and inflammatory factors that initiate HCMV reactivation in the host and allow the development of strategies to eradicate virus persistence.

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GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol.

Publications

GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol.

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