Muscarinic Regulation of Intracellular Signaling and Neurosecretion in Gonadotropin-Releasing Hormone Neurons

Krsmanović, Lazar Z.

doi:10.1210/en.139.10.4037

Cited by 39 publications

(32 citation statements)

References 29 publications

(29 reference statements)

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“…Compared with static cultures (42), this perifusion model presents the advantage of minimizing potential autocrine or paracrine effects occurring in vitro, because the effluent is continuously washed out of the chamber. We were also able to measure neurotransmitter secretion from a much lower number of neurons than previously reported using hypothalamic neurons adsorbed onto Biogel beads (43). This difference suggests that preservation of the neuronal network upon transfer into the perifusion chambers may result in increased cellular viability and possibly better preservation of normal cellular functions.…”

Section: Discussionmentioning

confidence: 78%

Interplay Between Galanin and Leptin in the Hypothalamic Control of Feeding via Corticotropin-Releasing Hormone and Neuropeptide Y

Bergonzelli¹,

Pralong²,

Glauser³

et al. 2001

Diabetes

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Over long periods, feeding and metabolism are tightly regulated at the central level. The total amount of nutrients ingested is thought to result from a delicate balance between orexigenic and anorexigenic factors expressed and secreted by specialized hypothalamic neuronal populations. We have developed a system of perifused hypothalamic neurons to characterize the relationships existing between the orexigenic peptide galanin and two other physiological modulators of feeding: neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH). We demonstrated that galanin stimulates CRH and NPY secretion from hypothalamic neurons in a dose-dependent manner. Exposure to leptin for 24 h before galanin stimulation decreased NPY secretion by 30%, leaving the responsiveness of CRH neurons intact. These results suggest that CRH and NPY neurons participate to the intrahypothalamic signaling pathway of galanin, an observation that can explain the lower potency of galanin to stimulate food intake in vivo compared with NPY. The differential effects exerted by leptin on CRH and NPY suggest that there exists a subset of NPY neurons that are exquisitely sensitive to marked variations in leptin levels, and that the CRH neurons are less responsive to increases in leptin concentrations. Diabetes 50:2666 -2672, 2001 R ecent evidence suggests that the central nervous system plays a key role in controlling food intake and metabolic adaptations (1). A delicate interplay seems to exist between the activities of highly specialized neuronal subpopulations involved in the regulation of feeding and energy storage, or of satiety and energy expenditure. Overall, these regulations, operating at the level of the central nervous system, achieve the tight control of energy balance observed in mammals (2). The neurons involved are mainly located within the hypothalamus, where they serve as central integrators of peripheral metabolic signals. One important function of leptin (3) seems to be informing these neurons about levels of energy stored in the body (4). Changes in circulating leptin levels can therefore trigger an appropriate response of the central nervous system to modulate food intake and metabolism according to the total amount of body fat (5) as well as the variations of energy balance (6).However, the relations between the different hypothalamic neuronal subpopulations seem to be extremely complex (1). The systems involved are redundant, and thus they are most difficult to individualize in vivo. Neuropeptide Y (NPY) and galanin can both elicit strong feeding behavior when injected centrally (7-10) and are expressed in hypothalamic areas associated with feeding and metabolic regulations (10 -12). NPY is one of the most abundant peptides of the hypothalamus (11) and remains among the most potent orexigenic factors (13). In addition, it has also been implicated in the control of neuroendocrine adaptations to fasting or unfavorable metabolic conditions (14,15). Like NPY, galanin plays a physiologically important role in the regulation of ne...

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Section: Discussionmentioning

confidence: 78%

Interplay Between Galanin and Leptin in the Hypothalamic Control of Feeding via Corticotropin-Releasing Hormone and Neuropeptide Y

Bergonzelli¹,

Pralong²,

Glauser³

et al. 2001

Diabetes

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“…1, B and C). GnRH receptors are primarily coupled to G q/11 proteins, but some of the physiological actions of GnRH are known to occur through activation of G s or G i proteins (5,33). In GT1-7 neurons, nanomolar GnRH concentrations cause marked elevation of inositol phosphate production through G q -mediated activation of phospholipase C and also stimulate cAMP production.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to regulating pituitary gonadotropin release, GnRH has extrapituitary actions in neural and nonneural tissues and in several types of tumor cells (1). Immortalized GnRH-producing neurons (GT1-7 neurons) express several G protein-coupled receptors (GPCRs), including those for GnRH and luteinizing hormone/ human chorionic gonadotropin (2,3), as well as ␣-and ␤-adrenergic (4), muscarinic (5), and serotonergic receptors (6). These cells retain many of the characteristics of the native GnRH neurons, including the ability to maintain pulsatile GnRH release (1,3).…”

mentioning

confidence: 99%

“…The major signal transduction pathways in cells expressing GnRH receptors are initiated by activation of phospholipase C. The consequent calcium (Ca 2ϩ ) mobilization and activation of protein kinase C (PKC) by GnRH are key elements in the hypothalamic control of gonadotropin secretion from the anterior pituitary gland (1,3,5). Activation of PKC and Ca 2ϩ mobilization during GnRH receptor stimulation are also responsible for mediating downstream signals leading to activation of extracellularly regulated mitogen-activated protein kinases (ERK1/2 MAPKs) that transmit signals from the cell surface to the nucleus to regulate transcriptional and other processes (7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

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Dependence of Gonadotropin-releasing Hormone-induced Neuronal MAPK Signaling on Epidermal Growth Factor Receptor Transactivation

Shah¹,

Soh²,

Catt³

2003

Journal of Biological Chemistry

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The hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH), utilizes multiple signaling pathways to activate extracellularly regulated mitogen-activated protein kinases (ERK1/2) in normal and immortalized pituitary gonadotrophs and transfected cells expressing the GnRH receptor. In immortalized hypothalamic GnRH neurons (GT1-7 cells), which also express GnRH receptors, GnRH, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA) caused marked phosphorylation of ERK1/2. This action of GnRH and PMA, but not that of EGF, was primarily dependent on activation of protein kinase C (PKC), and the ERK1/2 responses to all three agents were abolished by the selective EGF receptor kinase inhibitor, AG1478. Consistent with this, both GnRH and EGF increased tyrosine phosphorylation of the EGF receptor. GnRH and PMA, but not EGF, caused rapid phosphorylation of the proline-rich tyrosine kinase, Pyk2, at Tyr 402 . This was reduced by Ca 2؉ chelation and inhibition of PKC, but not by AG1478. GnRH stimulation caused translocation of PKC␣ and -⑀ to the cell membrane and enhanced the association of Src with PKC␣ and PKC⑀, Pyk2, and the EGF receptor. The Src inhibitor, PP2, the C-terminal Src kinase (Csk), and dominant-negative Pyk2 attenuated ERK1/2 activation by GnRH and PMA but not by EGF. These findings indicate that Src and Pyk2 act upstream of the EGF receptor to mediate its transactivation, which is essential for GnRH-induced ERK1/2 phosphorylation in hypothalamic GnRH neurons.

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“…Furthermore, oscillations in cAMP levels, regulated by cyclic nucleotide phosphodiesterases as well as activation of PKA have been implicated in a negative feedback mechanism involved in timing the pulsatile release of GnRH from GT1-7 cells (47,65). It has been suggested that acetylcholine modulates GnRH release from GT1-7 cells via increases in PLC and inhibition of cAMP through both muscarinic (M) 1 and M 2 receptors that are coupled to G q/11 and G i proteins respectively (66). Stimulation of PKC activity (61,62,67) and elevation of intracellular cGMP levels (68) have also been shown to enhance GnRH secretion from GT1-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Receptor Activation Regulates GnRH Gene Expression and Secretion in GT1–7 GnRH Neurons

Roy¹,

Belsham²

2002

Journal of Biological Chemistry

126

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Melatonin plays a significant role in the control of the hypothalamic-pituitary-gonadal axis. Using the GT1-7 cell line, an in vitro model of GnRH-secreting neurons of the hypothalamus, we examined the potential signal transduction pathways activated by melatonin directly at the level of the GT1-7 neuron. We found that melatonin inhibits forskolin-stimulated adenosine 3-, 5-cyclic monophosphate accumulation in GT1-7 cells through an inhibitory G protein. Melatonin induced protein kinase C activity by 1.65-fold over basal levels, increased the phosphorylation of extracellular signal-regulated kinase 1 and 2 proteins, and activated c-fos and junB mRNA expression in GT1-7 cells. Using the protein kinase A inhibitor H-89, the protein kinase C inhibitor bisindolylmaleimide, and the mitogen-activated protein kinase kinase inhibitor PD98059, we found that the melatonin-mediated cyclical regulation of GnRH mRNA expression may involve the protein kinase C and the extracellular signal-regulated kinase 1 and 2 pathways, but not the protein kinase A pathway. We found that melatonin suppresses GnRH secretion by ϳ45% in the GT1-7 neurons. However, in the presence of the inhibitors H-89, bisindolylmaleimide, and PD98059 melatonin was unable to suppress GnRH secretion. These results provide insights into the potential signal transduction mechanisms involved in the control of GnRH gene expression and secretion by melatonin.

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Muscarinic Regulation of Intracellular Signaling and Neurosecretion in Gonadotropin-Releasing Hormone Neurons

Cited by 39 publications

References 29 publications

Interplay Between Galanin and Leptin in the Hypothalamic Control of Feeding via Corticotropin-Releasing Hormone and Neuropeptide Y

Interplay Between Galanin and Leptin in the Hypothalamic Control of Feeding via Corticotropin-Releasing Hormone and Neuropeptide Y

Dependence of Gonadotropin-releasing Hormone-induced Neuronal MAPK Signaling on Epidermal Growth Factor Receptor Transactivation

Melatonin Receptor Activation Regulates GnRH Gene Expression and Secretion in GT1–7 GnRH Neurons

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