Melatonin Inhibits the Activation of Cyclic AMP‐Dependent Protein Kinase in Cultured Pars Tuberalis Cells from Ovine Pituitary

Hazlerigg, David G.; Morgan, Peter J.; Lawson, Wilfred; Hastings, Michael H.

doi:10.1111/j.1365-2826.1991.tb00324.x

Cited by 43 publications

(26 citation statements)

References 48 publications

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“…Consistent with this melatonin, which inhibits forskolin-induced cyclic AMP formation in PT cells, also inhibits forskolin-induced oPer1 expression ). Forskolin has also been shown to stimulate protein kinase A and the phosphorylation of CREB in PT cells, and this response is abrogated by melatonin (Hazlerigg et al 1991;McNulty et al 1994a). These results suggest a role for the cyclic AMP/PKA/CREB signal transduction pathway in the induction of Per1 gene expression through a CRE response element in the PT ).…”

Section: Introductionmentioning

confidence: 69%

The pars tuberalis as a target of the central clock

Ross¹,

Morgan²

2002

Cell Tissue Res

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The pars tuberalis (PT) of the pituitary has emerged from being a gland of obscure and unknown function to a tissue of central importance to our understanding of how photoperiod regulates seasonal responses. The discovery of melatonin receptors on this gland first pointed to its involvement in seasonal physiology. However, the more recent demonstration of the expression of clock genes in the PT, such as Per1, has heightened interest in the gland. Recent work shows how photoperiod, through the hormone melatonin, affects the timing and amplitude of expression of the Per1 gene, as well as other genes such as Icer. The effect of photoperiod and melatonin on the expression of Per1 in the PT is distinct to its effects on the SCN, and this probably reflects distinct functions of the clock genes in the two tissues - acting as part of the biological clock in the SCN, but as an interval timing system within the PT. The changes in amplitude of Per1 gene expression in response to altered length of photoperiod have provided the first clues as to how the durational melatonin signal is decoded within the neuroendocrine system.

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Section: Introductionmentioning

confidence: 69%

The pars tuberalis as a target of the central clock

Ross¹,

Morgan²

2002

Cell Tissue Res

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“…On SDS-PAGE (12.5%) 125I-iodoLH used as a reference ran with an apparent molecular weight 330 Morgan One consideration is the possibility that, despite the high extracellular levels applied, only submaximal levels were achieved in the intracellular compartment containing the relevant pools of protein kinase A. This problem is com pounded by the fact that in cells containing both isozymes of protein kinase A, as has been shown for pars tuberalis cells [33], there are four different cyclic AMP binding sites with which the analogues can potentially interact in order to achieve full activation. Since different analogues have different affinities for these sites it is probable that a single analogue may only achieve submaximal activation.…”

Section: Immunoprecipitation Of H I and Autoradiographical Localisatimentioning

confidence: 98%

p72, a Marker Protein for Melatonin Action in Ovine Pars tuberalis Cells: Its Regulation by Protein Kinase A and Protein Kinase C and Differential Secretion Relative to Prolactin

Morgan¹,

Barrett²,

Davidson³

et al. 1994

Neuroendocrinology

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The function of the pars tuberalis as a mediator of the action of melatonin remains elusive. As a direct method of assessing the potential role of secretory proteins, ovine pars tuberalis cells have been cultured and radiolabelled with ³⁵S-methionine, and the accumulation of specific radioactive products in the medium, measured after separation by SDS-PAGE and fluorography. The synthesis and secretion of a number of labelled proteins are increased by forskolin (1 µM) and inhibited dose dependently by melatonin (IC50, 300 pM), although consistently a 72-kD protein (p72), is the most intensely labelled of these. Thus, p72 acts as a useful marker of cellular activity for melatonin, whereas prolactin (p23) provides a melatonin non-responsive marker in ovine pars tuberalis cell cultures. The synthesis and secretion of p72 and other melatonin-sensitive proteins is regulated through the cyclic AMP/protein kinase A second-messenger pathway, as analogues of cyclic AMP mimic the action of forskolin, yet 1,9-dide-oxyforskolin, a forskolin analogue that is not active on adenylate cyclase, has no effect. However, the phorbol ester, phorbol-12, 13-myristate acetate, also regulates the synthesis and secretion of the same profile of proteins as forskolin indicating a potential role for protein kinase C, which occurs through an independent rather than a synergistic pathway. The differential effects of nocadazole (1 µM) and extracellular calcium depletion upon p72 and prolactin secretion indicates that p72 is secreted by a calcium and microtubule independent pathway, in contrast to prolactin. These observations in conjunction with the absence of dense-core storage vesicles in melatonin-responsive cells of the ovine PT are consistent with constitutive secretion of p72 from the latter and regulated secretion of prolactin from melatonin non-responsive cells. Using immunoprecipitation de novo synthesis and secretion of either LH or LH-like proteins from ovine pars tuberalis cells could not be detected under the conditions used. The absence of ¹²⁵I-(Des-Gly¹⁰ [D-Ala⁶]-LHRH-ethylamide) binding over most, but not all, of the ovine pars tuberalis supports the contention that the majority of the cells of the ovine pars tuberalis are not gonadotrophs. These results provide further support for the unique function for the pars tuberalis.

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“…In the PT, forskolin-stimulated cAMP synthesis has been shown to increase the activity of protein kinase A [21]. This increase in activity is likely to be involved in the observed enhanced level of phosphorylation of the cAMP response element binding protein (CREB) [22].…”

Section: Signal Transduction Mechanisms Regulated By Melatonin In Thementioning

confidence: 99%

Melatonin Receptors and Signal Transduction Mechanisms

Barrett¹,

Morris²,

Choi³

et al. 1999

Neurosignals

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The ovine pars tuberalis (PT) still offers the best model for the study of signal transduction pathways regulated by the melatonin receptor. From the evidence accumulated so far, it seems likely that the cAMP signal transduction pathway will be a major effector of a stimulatory signal to the PT which can be regulated by melatonin. Thus a principal action of melatonin in the PT may be the repression of biochemical processes driven by cAMP. However, through the phenomenon of sensitization, melatonin may also act to amplify a stimulatory input to the cAMP signal transduction pathway in the PT. These events are mediated via the melatonin receptor, which is itself a target for regulation by the melatonin signal. Studies using the PT have identified several signalling pathways that may serve to positively or negatively regulate the expression of the melatonin receptor. These and other studies in the PT have alluded to cAMP-independent pathways regulated by the melatonin receptor.

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Melatonin Inhibits the Activation of Cyclic AMP‐Dependent Protein Kinase in Cultured Pars Tuberalis Cells from Ovine Pituitary

Cited by 43 publications

References 48 publications

The pars tuberalis as a target of the central clock

The pars tuberalis as a target of the central clock

p72, a Marker Protein for Melatonin Action in Ovine Pars tuberalis Cells: Its Regulation by Protein Kinase A and Protein Kinase C and Differential Secretion Relative to Prolactin

Melatonin Receptors and Signal Transduction Mechanisms

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