Mechanism(s) by which the Transient Removal of Dopamine Regulation Potentiates the Prolactin-Releasing Action of Thyrotropin-Releasing Hormone

Escalera, Gonzálo Martínez de la; Weiner, Richard I.

doi:10.1159/000124912

Cited by 31 publications

(17 citation statements)

References 24 publications

(39 reference statements)

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“…Furthermore, as shown in figure 1, 100 n M TRH, which is able to stimulate PRL secretion 2- to 4-fold when administered to pituitary lactotropes and GH 4 C 1 /D 2 -DAR cells under the tonic action of DA (500 n M ), induced a significantly higher effect when administered to cells that were transiently cultured in the absence of DA for 30 min. These results are in agreement with previous studies demonstrating a potentiation of the PRL-releasing action of TRH by the stimulus represented by the escape from the tonic action of DA in vivo as well as in pituitary explants and pituitary cells in vitro [2, 3, 28, 29, 30, 31, 32, 33]. The finding that the same facilitation phenomenon can be observed in the pituitary tumor-derived cell line GH 4 C 1 transfected with a cDNA encoding the long form of the human D 2 -DA receptor supports the use of this homogeneous experimental model to analyze its mechanism of action.…”

Section: Resultssupporting

confidence: 93%

“…This facilitation could be the result of phosphorylation of the channels via the activation of PKA and PKC that follows the dissociation of DA from its receptors [2, 3]. In this study we have directly examined the effect of DA withdrawal on both PRL secretion and protein phosphorylation, using anterior pituitary lactotropes in primary culture and the lactotropic cell line GH 4 C 1 expressing human D 2 -DA receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Transient escapes from this tonic action of DA prime the PRL-releasing action of secretagogues such as thyrotropin-releasing hormone (TRH), resulting in secretory rates exceeding severalfold the response to the neuropeptide obtained under the persistent action of DA [1]. Previous work showed that the activation of adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase (protein kinase A or PKA) or of protein kinase C (PKC) is critical to the development of this potentiation [2, 3]. The involvement of voltage-activated Ca 2+ channels as putative substrates for PKA- and PKC-dependent phosphorylation was suggested by the finding that the enhancement of TRH action induced by the escape from DA is blocked by Ca 2+ channel antagonists such as methoxyverapamil and nifedipine [3].…”

Section: Introductionmentioning

confidence: 99%

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Potentiation of Prolactin Secretion following Lactotrope Escape from Dopamine Action

et al. 1999

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Modulation of Ca²⁺ channels has been shown to alter cellular functions. It can play an important role in the amplification of signals in the endocrine system, including the pleiotropically regulated pituitary lactotropes. Prolactin (PRL) secretion is tonically inhibited by dopamine (DA), the escape from which triggers acute episodes of hormone secretion. The magnitude of these episodes is explained by a potentiation of the PRL-releasing action of secretagogues such as thyrotropin-releasing hormone (TRH). While the mechanisms of this potentiation are not fully understood, it is known to be mimicked by the dihydropyridine, L-type Ca²⁺ channel agonist Bay K 8644 and blocked by nifedipine and methoxyverapamil. The potentiation is also blocked by inhibitors of cyclic AMP-dependent protein kinase and protein kinase C. We recently described that the escape from tonic actions of DA results in increased macroscopic Ca²⁺ currents in GH₄C₁ lactotropic clonal cells transfected with a cDNA encoding the long form of the human D₂-DA receptor. Here we show that the withdrawal from DA potentiates the PRL-releasing action of TRH in GH₄C₁/D₂-DAR cells to the same extent as in enriched lactotropes in primary culture. In both experimental models a low density of dihydropyridine receptors was shown by (+)-[³H]PN200-110 binding. Photoaffinity labelling with the dihydropyridine [³H]azidopine revealed a protein consistent with the α₁ subunit of L-type Ca²⁺ channels of 165–170 kDa. In both experimental models, the facilitation of TRH action triggered by the escape from DA was correlated with an enhanced rate of phosphorylation of this putative α₁ subunit, the nature of which was further supported by immunoprecipitation with selective antibodies directed against the α_1C and α_1D subunit of voltage-gated calcium channels. We propose that PKA- and PKC-dependent phosphorylation of the α₁ subunit of high voltage activated, L-type Ca²⁺ channels is responsible for the facilitation of Ca²⁺ currents in lactotropes, and hence for the potentiation of secretagogue-mediated PRL secretion. Thus, phosphorylation of Ca²⁺ channels in endocrine cells may be a mechanism for the regulation of various functions including amplification of hormone secretion.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potentiation of Prolactin Secretion following Lactotrope Escape from Dopamine Action

et al. 1999

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“…The molecular basis of these regulatory actions remains to be determined. Nevertheless, it is noteworthy the parallelism between the initial period of Ca 2+ current enhancement and the reported potentiation of the PRL secretory efficacy of TRH after DA removal in various different physiological conditions [6, 7, 37, 38, 39]. Furthermore, these effects were not associated with obvious changes in the time- and voltage-dependent properties of the current, suggesting that the alterations in Ca 2+ current density might depend on changes in the state of phosphorylation of the channels.…”

Section: Discussionmentioning

confidence: 99%

“…Episodes of massive PRL release, such as the surges of PRL in the afternoon of proestrus and in response to suckling in lactating animals, are preceded by a transient decrease in portal blood DA [2, 3, 4]. This brief escape from DA control increases the efficacy of secretagogues such as thyrotropin-releasing hormone (TRH) to stimulate PRL secretion [5, 6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Potentiation of Prolactin Secretion following Lactotrope Escape from Dopamine Action

et al. 1999

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Hypothalamic dopamine (DA) tonically inhibits prolactin (PRL) release from the anterior pituitary gland. Transient escapes from this DA tone elicit a pronounced potentiation of the PRL-releasing action of secretagogues such as thyrotropin-releasing hormone (TRH). Previous evidence has suggested that modulation of Ca²⁺ channels can be involved in this potentiation. With a lactotropic cell line (GH₄C₁) expressing human D₂-DA receptors, we tested the hypothesis that a brief escape from the tonic inhibitory action of DA triggers a facilitation of Ca²⁺ influx through Ca²⁺ channels. We initially found that in these cells, DA effectively and reversibly inhibited PRL secretion, and reversibly enhanced an inwardly rectifying K⁺ current. The effects of DA administration and withdrawal on Ca²⁺ currents were examined using the patch-clamp technique in the whole-cell configuration and Ba²⁺ as a divalent charge carrier through Ca²⁺ channels. Macroscopic Ba²⁺ currents were significantly decreased by short term (1–10 min) applications of DA (500 nM), which further declined following 24 h of constant exposure to DA. After DA removal, a biphasic facilitation of the density of Ba²⁺ currents was observed. An initial 2-fold enhancement of conductance was detected between 10 and 40 min, followed by a second facilitation of the same magnitude observed 24 h after DA withdrawal. The present results directly demonstrate that dissociation of DA from D₂-receptors expressed in GH₄C₁ lactotrope cells causes an increase of high-voltage-activated Ca²⁺ channel function, which may play an important role in the cross-talking amplification of endocrine cascades such as that involved in the TRH-induced PRL-release potentiating action of DA withdrawal.

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Neuroendocrine Regulation of Lactation and Milk Production

Crowley

2014

Comprehensive Physiology

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Prolactin (PRL) released from lactotrophs of the anterior pituitary gland in response to the suckling by the offspring is the major hormonal signal responsible for stimulation of milk synthesis in the mammary glands. PRL secretion is under chronic inhibition exerted by dopamine (DA), which is released from neurons of the arcuate nucleus of the hypothalamus into the hypophyseal portal vasculature. Suckling by the young activates ascending systems that decrease the release of DA from this system, resulting in enhanced responsiveness to one or more PRL-releasing hormones, such as thyrotropin-releasing hormone. The neuropeptide oxytocin (OT), synthesized in magnocellular neurons of the hypothalamic supraoptic, paraventricular, and several accessory nuclei, is responsible for contracting the myoepithelial cells of the mammary gland to produce milk ejection. Electrophysiological recordings demonstrate that shortly before each milk ejection, the entire neurosecretory OT population fires a synchronized burst of action potentials (the milk ejection burst), resulting in release of OT from nerve terminals in the neurohypophysis. Both of these neuroendocrine systems undergo alterations in late gestation that prepare them for the secretory demands of lactation, and that reduce their responsiveness to stimuli other than suckling, especially physical stressors. The demands of milk synthesis and release produce a condition of negative energy balance in the suckled mother, and, in laboratory rodents, are accompanied by a dramatic hyperphagia. The reduction in secretion of the adipocyte hormone, leptin, a hallmark of negative energy balance, may be an important endocrine signal to hypothalamic systems that integrate lactation-associated food intake with neuroendocrine systems.

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Mechanism(s) by which the Transient Removal of Dopamine Regulation Potentiates the Prolactin-Releasing Action of Thyrotropin-Releasing Hormone

Cited by 31 publications

References 24 publications

Potentiation of Prolactin Secretion following Lactotrope Escape from Dopamine Action

Potentiation of Prolactin Secretion following Lactotrope Escape from Dopamine Action

Potentiation of Prolactin Secretion following Lactotrope Escape from Dopamine Action

Neuroendocrine Regulation of Lactation and Milk Production

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