Dual-Level Afferent Control of Growth Hormone-Releasing Hormone (GHRH) Neurons in GHRH–Green Fluorescent Protein Transgenic Mice

Baccam, Nelly; Alonso, Gérard; Costecalde, Thomas; Fontanaud, Pierre; Molino, François; Robinson, I. C. A. F.; Mollard, Patrice; Méry, Pierre‐François

doi:10.1523/jneurosci.2693-06.2007

Cited by 17 publications

(32 citation statements)

References 46 publications

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“…Moreover, in situ mRNA hybridization studies showed that GHRH neurons of the arcuate nucleus, the primary site of GHRH synthesis and storage in mice (35), also express M 3 mAChRs. In agreement with this observation, a recent electrophysiological study demonstrated that GHRH neurons are endowed with functional mAChRs, activation of which leads to enhanced action potential firing (36).…”

Section: Discussionsupporting

confidence: 64%

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Gautam

Jeon²,

Starost³

et al. 2009

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

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The molecular pathways that promote the proliferation and maintenance of pituitary somatotrophs and other cell types of the anterior pituitary gland are not well understood at present. However, such knowledge is likely to lead to the development of novel drugs useful for the treatment of various human growth disorders. Although muscarinic cholinergic pathways have been implicated in regulating somatotroph function, the physiological relevance of this effect and the localization and nature of the receptor subtypes involved in this activity remain unclear. We report the surprising observation that mutant mice that selectively lack the M3 muscarinic acetylcholine receptor subtype in the brain (neurons and glial cells; Br-M3-KO mice) showed a dwarf phenotype associated with a pronounced hypoplasia of the anterior pituitary gland and a marked decrease in pituitary and serum growth hormone (GH) and prolactin. anterior pituitary gland ͉ dwarfism ͉ knockout mice V arious neurotransmitter systems have been implicated in regulating somatotroph function and growth hormone (GH) secretion, either by acting on the anterior pituitary gland directly or by modulating the release of GH-releasing hormone (GHRH) or somatostatin from the hypothalamus (for a comprehensive review, see ref. 1). However, the physiological relevance of the individual pathways and the identity and localization of the receptor subtypes involved in mediating these effects are not well understood in most cases.Pharmacological studies suggest that central muscarinic cholinergic pathways play a role in stimulating GH release in experimental animals and humans (1-9). The identification of the molecular pathways and the specific muscarinic ACh receptor (mAChR) subtypes involved in mediating these responses should be of considerable potential therapeutic interest. However, work in this area has been complicated by the existence of 5 molecularly distinct mAChR subtypes (M 1 -M 5 ) that are difficult to distinguish by classical pharmacological tools (10, 11). Moreover, virtually all brain regions express multiple mAChRs in a complex, overlapping pattern (12-15).The M 3 mAChR subtype is expressed at relatively high levels in the hypothalamus but is also found in many other brain regions (16-18). At present, little is known about the physiological relevance of these neuronal M 3 mAChRs. To shed light on this issue, we used Cre/loxP technology to generate a set of mutant mice, referred to as Br-M3-KO mice, that selectively lacked the M 3 mAChR subtype in the brain (neurons and glial cells). Strikingly, Br-M3-KO mice showed a dwarf phenotype, associated with a dramatic reduction in the size of the anterior pituitary gland, a marked decrease in pituitary GH and prolactin levels, and significantly reduced serum GH, insulin-like growth factor-1 (IGF-1), and prolactin levels. Remarkably, treatment of Br-M3-KO mice with CJC-1295, a synthetic GHRH analog (19-21), restored normal pituitary size, serum GH and IGF-1 levels, and longitudinal growth. These data reveal an unexpect...

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Section: Discussionsupporting

confidence: 64%

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Gautam

Jeon²,

Starost³

et al. 2009

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

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“…GABA also modulates GHRH neurons [27], so its potential involvement in the effect of ghrelin on GHRH neurons was studied. Fig.…”

Section: Resultsmentioning

confidence: 99%

Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus

et al. 2010

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BackgroundGhrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin.Principal FindingsHere, we show that ghrelin stimulates the firing rate of identified GHRH neurons, in transgenic GHRH-GFP mice. This stimulation is prevented by growth hormone secretagogue receptor-1 antagonism as well as by U-73122, a phospholipase C inhibitor and by calcium channels blockers. The effect of ghrelin does not require synaptic transmission, as it is not antagonized by γ-aminobutyric acid, glutamate and NPY receptor antagonists. In addition, this hypothalamic effect of ghrelin is independent of somatostatin, the inhibitor of the GH axis, since it is also found in somatostatin knockout mice. Indeed, ghrelin does not modify synaptic currents of GHRH neurons. However, ghrelin exerts a strong and direct depolarizing effect on GHRH neurons, which supports their increased firing rate.ConclusionThus, GHRH neurons are a specific target for ghrelin within the brain, and not activated secondary to altered activity in feeding circuits. These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.

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“…50). Mature (14-16 d in vitro) hippocampal neurons expressing the transfection marker ZsGreen were visualized and recorded with the patch-clamp technique, as previously described (51). After establishing the whole-cell configuration, MEA-TMA (100 μM) was briefly applied onto the neuron from a glass pipet, located at <100-μm distance from the cell body.…”

Section: Methodsmentioning

confidence: 99%

Optical control of an ion channel gate

Lemoine

Habermacher

Martz

et al. 2013

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

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The powerful optogenetic pharmacology method allows the optical control of neuronal activity by photoswitchable ligands tethered to channels and receptors. However, this approach is technically demanding, as it requires the design of pharmacologically active ligands. The development of versatile technologies therefore represents a challenging issue. Here, we present optogating, a method in which the gating machinery of an ATP-activated P2X channel was reprogrammed to respond to light. We found that channels covalently modified by azobenzene-containing reagents at the transmembrane segments could be reversibly turned on and off by light, without the need of ATP, thus revealing an agonist-independent, light-induced gating mechanism. We demonstrate photocontrol of neuronal activity by a light-gated, ATP-insensitive P2X receptor, providing an original tool devoid of endogenous sensitivity to delineate P2X signaling in normal and pathological states. These findings open new avenues to specifically activate other ion channels independently of their natural stimulus.azobenzene photoswitch | purinergic receptors O ptogenetic approaches in neuroscience rely on the heterologous expression of engineered light-gated ion channels or pumps to trigger or inhibit electrical activity of selected neurons (1, 2). This powerful and revolutionizing technique provides an exquisite remote control of neuronal circuits that drive behavior in animals. Of special interest is the optogenetic pharmacology (also known as optochemical genetic) (3, 4), which allows the control of an ion channel or receptor function by a photoswitchable ligand that is irreversibly tethered to the genetically modified protein through cysteine substitution (3, 4). Ligands are pharmacologically active substances targeting either competitive (5-7), or noncompetitive binding sites (8-10), and light sensitivity is mostly conferred by substituting a photoisomerizable azobenzene derivative, which interconverts reversibly between a long trans-isomer and a short cis-isomer (11). However, this approach is technically demanding, as it requires the design of site-specific ligands for each target. The development of versatile methods with generic photoswitchable molecules would thus improve the optochemical strategy.Here, we present optogating, a unique method for the optical control of ATP-activated P2X channel gating. P2X receptors are a family of trimeric, cation-selective channels (12, 13) comprising seven mammalian subtypes that mediate a variety of physiological responses, including fast synaptic transmission, contraction of smooth muscle, modulation of neurotransmitter release, and pain sensation (12,14,15). P2X receptors are considered as emerging therapeutic targets because of their link to cancer (16), inflammatory (17), and neuronal diseases, including neuropathic pain (18). Inspired by previous works showing that chemical modification of the transmembrane (TM) pore region of the P2X2 receptor affects channel gating through labeling of single cysteine mutants by p...

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Dual-Level Afferent Control of Growth Hormone-Releasing Hormone (GHRH) Neurons in GHRH–Green Fluorescent Protein Transgenic Mice

Cited by 17 publications

References 46 publications

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus

Optical control of an ion channel gate

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Dual-Level Afferent Control of Growth Hormone-Releasing Hormone (GHRH) Neurons in GHRH–Green Fluorescent Protein Transgenic Mice

Cited by 17 publications

References 46 publications

Neuronal M 3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Neuronal M 3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus

Optical control of an ion channel gate

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Product

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Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

Neuronal M ₃ muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth