Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line.

Escalera, Gonzálo Martínez de la; Choi, Amy L. H.; Weiner, Richard I.

doi:10.1073/pnas.89.5.1852

Cited by 235 publications

(142 citation statements)

References 21 publications

(30 reference statements)

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“…A second interpretation could be that the neurotransmitters released from afferent inputs signal by increasing intracellular cAMP levels in GnRH neurons. For example, vasoactive intestinal peptide (VIP) 2 receptors that are positively coupled to adenylate cyclase are expressed by rat GnRH neurons (36). Central administration of an antiserum to VIP delays and attenuates the LH surge (37).…”

Section: Discussionmentioning

confidence: 99%

“…Further complicating the understanding of these questions is the complexity of the neural connectivity of GnRH neurons. The development of the highly differentiated GT1 GnRH neuronal cell lines (1) and the demonstration that pulsatile release was an intrinsic property of the cells provided a model to study molecular events underlying pulsatile GnRH release (2)(3)(4). However, one is always faced with the problem of translating findings from an immortalized cell line to the physiological setting.…”

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confidence: 99%

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Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Paruthiyil

Majdoubi

Conti

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Experiments in the GT1 gonadotropin-releasing hormone (GnRH) cell line have shown that the cAMP signaling pathway plays a central role in regulating the excitability of the cells. Lowering cAMP levels by expressing the constitutively active cAMP-specific phosphodiesterase PDE4D1 in GT1 cells inhibited spontaneous Ca 2؉ oscillations and intrinsic pulsatile GnRH secretion. To address the role of cAMP levels in endogenous GnRH neurons, we genetically targeted expression of PDE4D1 (P) to GnRH neurons in transgenic rats (R) by using the GnRH gene promoter͞enhancer regions (G). Three lines of transgenic rats, GPR-2, -4, and -5, were established. In situ hybridization and RT-PCR studies demonstrated that transgene expression was specifically targeted to GnRH neurons. Decreased fertility was observed in female but not in male rats from all three lines. The mean luteinizing hormone (LH) levels in ovariectomized rats were significantly reduced in the GPR-4 and -5 lines but not in the GPR-2 line. In castrated male and female GPR-4 rats, the LH pulse frequency was dramatically reduced. Six of twelve GPR-4 females studied did not ovulate and had polycystic ovaries. The remaining six females ovulated, but the magnitude of the preovulatory LH surge was inhibited by 63%. These findings support the hypothesis that cAMP signaling may play a central role in regulating excitability of GnRH neurons in vivo. The GPR-4 line of transgenic rats provides a genetic model for the understanding of the role of pulsatile gonadotropin release in follicular development.T he pulsatile release of gonadotropin-releasing hormone (GnRH) underlies reproductive function in male and female mammals. Understanding the molecular mechanisms regulating pulsatile GnRH secretion has been hampered by the low number of GnRH neurons and their scattered localization throughout the preoptic area in rodents. Further complicating the understanding of these questions is the complexity of the neural connectivity of GnRH neurons. The development of the highly differentiated GT1 GnRH neuronal cell lines (1) and the demonstration that pulsatile release was an intrinsic property of the cells provided a model to study molecular events underlying pulsatile GnRH release (2-4). However, one is always faced with the problem of translating findings from an immortalized cell line to the physiological setting. We have attempted to bridge observations made in GT1 cells regarding signaling events regulating GnRH pulsatility to the physiological setting by developing a transgenic rat model. We used an established genetic approach to alter the activity of a signaling pathway that could be used in parallel experiments in GT1 cells and transgenic rats. Transgenic rats, unlike transgenic mice, permit the reliable analysis of pulsatile luteinizing hormone (LH) release that closely mimics pulsatile GnRH release in castrated animals (5).The secretion of GnRH in GT1 neurons is stimulated by elevations in cAMP levels (6-8). The stimulation of GnRH secretion by elevated cAMP levels appears to...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Paruthiyil

Majdoubi

Conti

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…The murine pancreatic insulinoma bTC3 cell line [19], a gift from Dr D. Hanahan, University of California San Francisco, was used in all experiments except if otherwise indicated. We used GT1.7, a gonadotropin-releasing hormone secreting tumour cell line with a strong neuronal phenotype [20], a gift from Dr R. Weiner, University of California San Francisco, for the characterisation of glima 38 in cells of neuronal origin. The preparation of radiolabelled detergent phase purified membrane proteins was done as described previously [4] except that the Triton X-114 detergent phase [21] of the particulate fraction (PFDP) was subjected to an additional ultracentrifugation at 100 000 g to remove aggregates.…”

Section: Methodsmentioning

confidence: 99%

Peptide mapping and characterisation of glycation patterns of the glima 38 antigen recognised by autoantibodies in Type I diabetic patients

et al. 2000

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“…An intrinsic mechanism for generating pulsatile secretion within individual GnRH neurons may exist. Pulsatile GnRH release has been demonstrated in immortalized GnRH-producing GT1 cells and in embryonic GnRH neuronal cultures (6,7). Intracellular calcium oscillation (8), episodic gene expression coupled with exocytic activity (9, 10), voltage-dependent ion channel-mediated synchronization (11), and cellular circadian oscillators (12) have been implicated in pulsatile secretion of GnRH.…”

mentioning

confidence: 99%

Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

Choe

Kim

Park

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) is essential for pituitary gonadotrope function. Although the importance of pulsatile GnRH secretion has been recognized for several decades, the mechanisms underlying GnRH pulse generation in hypothalamic neural networks remain elusive. Here, we demonstrate the ultradian rhythm of GnRH gene transcription in single GnRH neurons using cultured hypothalamic slices prepared from transgenic mice expressing a GnRH promoter-driven destabilized luciferase reporter. Although GnRH promoter activity in each GnRH neuron exhibited an ultradian pattern of oscillations with a period of ∼10 h, GnRH neuronal cultures exhibited partially synchronized bursts of GnRH transcriptional activity at ∼2-h intervals. Surprisingly, pulsatile administration of kisspeptin, a potent GnRH secretagogue, evoked dramatic synchronous activation of GnRH gene transcription with robust stimulation of pulsatile GnRH secretion. We also addressed the issue of hierarchical interaction between the circadian and ultradian rhythms by using Bmal1 -deficient mice with defective circadian clocks. The circadian molecular oscillator barely affected basal ultradian oscillation of GnRH transcription but was heavily involved in kisspeptin-evoked responses of GnRH neurons. In conclusion, we have clearly shown synchronous bursts of GnRH gene transcription in the hypothalamic GnRH neuronal population in association with episodic neurohormone secretion, thereby providing insight into GnRH pulse generation.

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Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line.

Cited by 235 publications

References 21 publications

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Peptide mapping and characterisation of glycation patterns of the glima 38 antigen recognised by autoantibodies in Type I diabetic patients

Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

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