Activation of LH receptors expressed in GnRH neurons stimulates cyclic AMP production and inhibits pulsatile neuropeptide release

Mores, Nadia

doi:10.1210/en.137.12.5731

Cited by 21 publications

(23 citation statements)

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“…Also, in hypothalamic neuronal GT1-7 cells, the elevation of intracellular cAMP levels by forskolin or application of 8-bromo-cAMP was found to mimic GnRH receptor activation by stimulating neurosecretion (24). Some recent reports have shown that GnRH can activate the G s -coupled adenylyl cyclase pathway.…”

mentioning

confidence: 85%

Mediation of Cyclic AMP Signaling by the First Intracellular Loop of the Gonadotropin-releasing Hormone Receptor

Arora

Krsmanović

et al. 1998

Journal of Biological Chemistry

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The gonadotropin-releasing hormone (GnRH) receptor, which is a unique G protein-coupled receptor without a C-terminal cytoplasmic domain, activates both inositol phosphate (InsP) and cAMP signaling responses. The function of the highly basic first intracellular (1i) loop of the GnRH receptor in signal transduction was evaluated by mutating selected residues located in its N and C termini. Replacements , and Leu 80 at the C terminus, caused no change in binding affinity. The agonist-induced InsP and cAMP responses of the Q61E and K59Q,K62Q receptors were also unaffected, but the L58A receptor showed a normal InsP response and an 80% decrease in cAMP production. At the C terminus, the InsP response of the L73R receptor was normal, but cAMP production was reduced by 80%. The EC 50 for GnRH-induced InsP responses of the S74E and L80A receptors was increased by about one order of magnitude, and the cAMP responses were essentially abolished. These findings indicate that cAMP signaling from the GnRH receptor is dependent on specific residues in the 1i loop that are not essential for activation of the phosphoinositide signaling pathway.A wide variety of neurotransmitters, peptide and protein hormones, chemokines, growth factors, and other ligands elicit specific cellular responses by binding to plasma membrane receptors that are coupled to one or more heterotrimeric guanine nucleotide binding/regulatory proteins (G proteins). The primary signaling pathways for many of these receptors have been elucidated (1, 2). Agonist binding to a specific receptor on the cell surface causes a conformational change in the receptor that allows it to interact with its cognate G protein, stimulating guanine nucleotide exchange on the ␣ subunit of the G protein.The release of the ␣ subunit-GTP and ␤␥ subunits from the receptor-G protein complex, and the activation of effector systems including phospholipase C, adenylyl cyclase, and ion channels, regulate the intracellular levels of inositol phosphate, calcium, cyclic AMP, and other second messengers.Although most G protein-coupled receptors (GPCRs) 1 share a common structure, based on seven membrane-spanning domains, relatively little is known about the functional significance of this arrangement. It probably provides structural and functional integrity to the receptor, and the presence of several conserved amino acid residues in the transmembrane regions and cytoplasmic loops may reflect their role in agonist-induced G protein coupling and signal generation. Mutagenesis and chimeric studies with several receptor-G protein pairs, including the ␤-adrenergic-G s , muscarinic acetylcholine-G i , angiotensin II-G q , and rhodopsin-G t , have implicated the N-and Cterminal portions of the third intracellular (3i) loop of the receptors in G protein activation and signal transduction (3-11). In the case of the thyroid stimulating hormone (TSH) receptor-G s , dopamine (D1) receptor-G s , and rhodopsin-G t , regions within the cytoplasmic tail have also been found to interact with G proteins (12...

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mentioning

confidence: 85%

Mediation of Cyclic AMP Signaling by the First Intracellular Loop of the Gonadotropin-releasing Hormone Receptor

Arora

Krsmanović

et al. 1998

Journal of Biological Chemistry

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“…An unexpected finding is that the medial pallium, a hippocampal homolog in anurans, does not express LHR, whereas the mammalian hippocampus shows the highest levels of expression of LHR (4). Although the functional significance of this species difference is not understood, expression of LHRs in hypothalamic areas, highly conserved among vertebrates, is likely to participate in the well established role of providing negative feedback to GnRH cell populations (10). Support for this hypothesis comes from the presence of GnRH-expressing cells in the POA and median eminence in the Xenopus brain, where LHRs are also expressed (40).…”

Section: Distribution and Functionality Of Lhrs In Comparison With Othermentioning

confidence: 99%

“…Based on these receptor distributions, several functions for LHRs have been hypothesized, including regulation of GnRH expressing cells (9)(10)(11), sensory information processing (12), modulation of hippocampal activity (8,13) and pathology (14), and neurosteroidogenesis (12). However, with the exception of the role of LHRs in regulating GnRH, direct in vivo tests for the function of gonadotropins within the CNS are few and include effects on the sleepwake cycle, activity, and stereotypic behavior in female rodents (15,16).…”

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confidence: 99%

Direct action of gonadotropin in brain integrates behavioral and reproductive functions

Yang¹,

Nasipak²,

Kelley

2007

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

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Essential roles for gonadotropins in gonadal development and reproduction are well established. Over the past decade, however, the expression of luteinizing hormone receptor (LHR) has also been reported in the brain of various mammals and birds. Although suggestive, it has not yet been determined whether this expression pattern supports a novel function for gonadotropins. Here, we demonstrate a CNS-mediated role of gonadotropins in a reproductive behavior: the courtship songs of the South African clawed frog, Xenopus laevis. Male advertisement calling in this species depends on a nongonadal action of gonadotropin. To determine whether this effect is due to action on the CNS, we administered gonadotropin intracerebroventricularly (ICV) or systemically to intact or castrated males with or without concomitant androgen replacement. In intact and androgen-replaced gonadectomized males, gonadotropin significantly increased calling within 1 h after ICV injection. The effective dosage via ICV injections was less than one hundredth of the effective systemic dose. In situ hybridization with a cloned fragment of Xenopus LHR revealed strong expression in ventral forebrain areas important for vocal control. Further, gonadotropin treatment of brain in vitro up-regulates immunoreactivity for the LHR downstream target, egr-1, specifically in these vocal forebrain areas. Up-regulation occurs even when synaptic transmission is suppressed by incubation in Ca 2؉ free/high magnesium saline. These results demonstrate a neural role for gonadotropin in the control of calling behavior, potentially mediated via LHRs in forebrain vocal nuclei. Gonadotropin may play a novel integrative role in modulating both reproductive physiology and behavior.amphibian ͉ luteinizing hormone receptor ͉ neural action ͉ neuromodulator G onadotropins [luteinizing hormone (LH) in particular] play important roles in reproductive physiology across vertebrates. These heterodimeric glycoprotein hormones are typically released from the anterior pituitary in response to gonadotropin releasing hormone (GnRH), although some [e.g., human CG (hCG)] are produced in the placenta (1). LH and hCG stimulate the production of gonadal steroids, and exert their effects through binding to the same seven transmembrane domain G protein-coupled receptor (LHR, (1)). Until recently, LHR expression was believed to be confined to the gonads where it is required for fertility (for a review, see ref.2). However, recent findings of LHR expression in neural tissues in birds (3) and mammals (4), including humans (5-7), suggest potentially important functions for gonadotropins via direct action in the brain (8).To date, neural expression of LHRs in various mammalian and avian species has been documented in the hypothalamus, hippocampus, brainstem, cortex, choroid plexus, and pituitary (4). Based on these receptor distributions, several functions for LHRs have been hypothesized, including regulation of GnRH expressing cells (9-11), sensory information processing (12), modulation of hippocam...

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“…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%

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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Activation of LH receptors expressed in GnRH neurons stimulates cyclic AMP production and inhibits pulsatile neuropeptide release

Cited by 21 publications

References 0 publications

Mediation of Cyclic AMP Signaling by the First Intracellular Loop of the Gonadotropin-releasing Hormone Receptor

Mediation of Cyclic AMP Signaling by the First Intracellular Loop of the Gonadotropin-releasing Hormone Receptor

Direct action of gonadotropin in brain integrates behavioral and reproductive functions

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

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