Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor

Knollman, Paul E.; Conn, P. Michael

doi:10.1016/j.abb.2008.05.011

Cited by 11 publications

(8 citation statements)

References 35 publications

(38 reference statements)

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“…GnRH initiates response at the anterior pituitary cells by binding to a family of membrane receptors called G-protein coupled receptors which stimulate the downstream responses by coupling to G-protein on the cell membrane. Multiple activation of G-protein subtypes by a single receptor and the subsequent cross-talk between their corresponding signalling pathways leading to multiple physiological functions have been observed in experiments [21,27]. Feedback of ovarian hormones also play a part in controlling the pituitary response to GnRH; in particular, both estrogen and inhibin have been reported to exert negative feedback on FSH release and secretion with estrogen playing the greater role in the control of FSH concentration levels [1,26,38].…”

Section: Introductionmentioning

confidence: 99%

A mathematical model for the human menstrual cycle

Chen

Ward

2013

Mathematical Medicine and Biology

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• This is a pre-copyedited, author-produced PDF of an article accepted for publication in Mathematical Medicine and Biology following peer review.The January 18, 2013Abstract A simple mathematical model framework is developed to describe the hormonal interactions of the human menstrual cycle along the hypothalamus-pituitary-ovaries axis. The framework is designed so that it can be readily extended to model processes that disrupt the normal functioning cycle. The model in its most basic formulation exhibits multiple periodic solutions, one of which shows the key characteristics of a menstrual cycle, whilst the others indicate possible abnormalities sometimes observed in women of reproductive age. The basic model is extended to encompass receptor down-regulation as a mechanism to describe the desensitisation of the pituitary to continuous stimulation of hypothalamic hormone, a hormonal therapy that is commonly prescribed prior to the surgical procedure for the removal of uterine myomas. Though the mechanisms for desensitisation are likely to be more complex, the model results are in good qualitative agreement with physiological observations.

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Section: Introductionmentioning

confidence: 99%

A mathematical model for the human menstrual cycle

Chen

Ward

2013

Mathematical Medicine and Biology

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“…The phenomenon that individual receptors are able to activate multiple pathways by switching between different G proteins is well established [38,39]. The coupling of betaadrenergic receptors to G s proteins leads to the activation of adenylate cyclase and the consequent phosphorylation of protein kinase A, which phosphorylates the receptor and diminishes its coupling to G s but increases the coupling to G i .…”

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confidence: 99%

Nociceptin Inhibits Uterine Contractions in Term-Pregnant Rats by Signaling Through Multiple Pathways1

Klinke

Tekes

Gunduz-Cinar

et al. 2010

Biology of Reproduction

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The actions of the endogenous peptide nociceptin (PNOC; previously abbreviated as N/OFQ) on the myometrium have not been investigated previously. Our aim was to study the presence and functional role of PNOC in the modulation of uterine contractility in pregnant rats at term. The presence of PNOC and its receptors (OPRL1; previously called NOP) in the uterus were detected by radioimmunoassay and radioligand-binding experiments. The PNOC-stimulated G protein activation was assessed by a [(35)S]GTPgammaS-binding technique. The effects of PNOC in uterine rings precontracted with KCl or oxytocin were also tested in vitro. Uterine levels of cAMP were measured by enzyme immunoassay. The K(+) channel blockers tetraethylammonium and paxilline were used to study the role of K(+) channels in mediating the uterine effects of PNOC. Both PNOC and OPRL1 were present in the uterus. PNOC revealed a maximum contraction inhibition of approximately 30%, which was increased to 40% by naloxone. Naloxone and pertussis toxin significantly attenuated the G protein-stimulating effect of PNOC. The uterine cAMP levels were elevated by PNOC and naloxone and after preincubation with pertussis toxin. Tetraethylammonium and paxilline reduced the contraction-inhibiting effect of PNOC and naloxone to approximately 10% and 15%, respectively. We presume that PNOC plays a role in regulating uterine contractility at term. Its effect is mediated partly by stimulatory heterotrimeric G (G(s)) proteins coupled to OPRL1 receptors and elevated cAMP levels, and also by Ca(2+)-dependent K(+) channels. Our results demonstrate a novel action and signaling pathway for PNOC that might be a potential drug target.

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“…The primary transduction mechanism utilized by the GnRHR is via coupling to Gα q/11 G proteins. Coupling to the cAMP pathway has also been observed but this has been attributed to the overexpression of exogenous receptor in transfected cells [47], since it typically does not occur in human gonadotrope cells [5]. Indeed, cAMP production may be achieved with non-human GnRHR due to a specific motif in the C-terminal tail [48], which is lacking in the human receptor [49].…”

Section: Discussionmentioning

confidence: 99%

GnRH Antagonists Produce Differential Modulation of the Signaling Pathways Mediated by GnRH Receptors

Sperduti

Limoncella

Lazzaretti

et al. 2019

IJMS

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Commercial gonadotropin-releasing hormone (GnRH) antagonists differ by 1–2 amino acids and are used to inhibit gonadotropin production during assisted reproduction technologies (ART). In this study, potencies of three GnRH antagonists, Cetrorelix, Ganirelix and Teverelix, in inhibiting GnRH-mediated intracellular signaling, were compared in vitro. GnRH receptor (GnRHR)-transfected HEK293 and neuroblastoma-derived SH-SY5Y cell lines, as well as mouse pituitary LβT2 cells endogenously expressing the murine GnRHR, were treated with GnRH in the presence or absence of the antagonist. We evaluated intracellular calcium (Ca2+) and cAMP increases, cAMP-responsive element binding-protein (CREB) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation, β-catenin activation and mouse luteinizing-hormone β-encoding gene (Lhb) transcription by bioluminescence resonance energy transfer (BRET), Western blotting, immunostaining and real-time PCR as appropriate. The kinetics of GnRH-induced Ca2+ rapid increase revealed dose-response accumulation with potency (EC50) of 23 nM in transfected HEK293 cells, transfected SH-SY5Y and LβT2 cells. Cetrorelix inhibited the 3 × EC50 GnRH-activated calcium signaling at concentrations of 1 nM–1 µM, demonstrating higher potency than Ganirelix and Teverelix, whose inhibitory doses fell within the 100 nM–1 µM range in both transfected HEK293 and SH-SY5Y cells in vitro. In transfected SH-SY5Y, Cetrorelix was also significantly more potent than other antagonists in reducing GnRH-mediated cAMP accumulation. All antagonists inhibited pERK1/2 and pCREB activation at similar doses, in LβT2 and transfected HEK293 cells treated with 100 nM GnRH. Although immunostainings suggested that Teverelix could be less effective than Cetrorelix and Ganirelix in inhibiting 1 µM GnRH-induced β-catenin activation, Lhb gene expression increase occurring upon LβT2 cell treatment by 1 µM GnRH was similarly inhibited by all antagonists. To conclude, this study has demonstrated Cetrorelix-, Ganirelix- and Teverelix-specific biased effects at the intracellular level, not affecting the efficacy of antagonists in inhibiting Lhb gene transcription.

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Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor

Cited by 11 publications

References 35 publications

A mathematical model for the human menstrual cycle

A mathematical model for the human menstrual cycle

Nociceptin Inhibits Uterine Contractions in Term-Pregnant Rats by Signaling Through Multiple Pathways1

GnRH Antagonists Produce Differential Modulation of the Signaling Pathways Mediated by GnRH Receptors

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