Ghrelin Indirectly Activates Hypophysiotropic CRF Neurons in Rodents

Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), La Plata, Buenos Aires, Argentina.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e31462. DOI: 10.1371/journal.pone.0031462
Source: PubMed


Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine function by acting on its receptor, GHSR (Growth Hormone Secretagogue Receptor). Recent evidence indicates that a key function of ghrelin is to signal stress to the brain. It has been suggested that one of the potential stress-related ghrelin targets is the CRF (Corticotropin-Releasing Factor)-producing neurons of the hypothalamic paraventricular nucleus, which secrete the CRF neuropeptide into the median eminence and activate the hypothalamic-pituitary-adrenal axis. However, the neural circuits that mediate the ghrelin-induced activation of this neuroendocrine axis are mostly uncharacterized. In the current study, we characterized in vivo the mechanism by which ghrelin activates the hypophysiotropic CRF neurons in mice. We found that peripheral or intra-cerebro-ventricular administration of ghrelin strongly activates c-fos--a marker of cellular activation--in CRF-producing neurons. Also, ghrelin activates CRF gene expression in the paraventricular nucleus of the hypothalamus and the hypothalamic-pituitary-adrenal axis at peripheral level. Ghrelin administration directly into the paraventricular nucleus of the hypothalamus also induces c-fos within the CRF-producing neurons and the hypothalamic-pituitary-adrenal axis, without any significant effect on the food intake. Interestingly, dual-label immunohistochemical analysis and ghrelin binding studies failed to show GHSR expression in CRF neurons. Thus, we conclude that ghrelin activates hypophysiotropic CRF neurons, albeit indirectly.

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    • "channels affects neurotransmitter release in hypothalamic GABAergic neurons. This is particularly relevant, as it has been reported that -amino butyric acid (GABA) release is essential for regulating food intake (Wu et al., 2009), and that GHSR1a activity decreases inhibitory input of hypothalamic networks (Cabral et al., 2012). To make such studies density by GPCRs was reported previously for Ca v 2.2 channels complexed with nociceptin (ORL1) and dopamine (D1 and D2) receptors (Zamponi, 2015). "
    The Journal of General Physiology 09/2015; 146(3). DOI:10.1085/jgp.201511462 · 4.79 Impact Factor
    • "GHSR1a is found at presynaptic terminals ( Cowley et al . , 2003 ; Yang et al . , 2011 ) . It has also been shown that GABA release by AgRP ARC neurons is required for ghrelin - induced food intake ( Tong et al . , 2008 ) , and a ghrelin - induced reduction of GABA release has been proposed to mediate other hypo - thalamic actions of the hormone ( Cabral et al . , 2012 ) . Thus , current results showing that ghrelin - induced GHSR1a activity inhibits native calcium channels , im - pairs Ca V 2 - dependent GABA release from ARC explants , and modifies synaptic activity in hypothalamic neurons in culture offer a molecular mechanism that could medi - ate well - established effects of ghrelin . In contras"
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    ABSTRACT: The growth hormone secretagogue receptor type 1a (GHSR1a) has the highest known constitutive activity of any G protein-coupled receptor (GPCR). GHSR1a mediates the action of the hormone ghrelin, and its activation increases transcriptional and electrical activity in hypothalamic neurons. Although GHSR1a is present at GABAergic presynaptic terminals, its effect on neurotransmitter release remains unclear. The activities of the voltage-gated calcium channels, CaV2.1 and CaV2.2, which mediate neurotransmitter release at presynaptic terminals, are modulated by many GPCRs. Here, we show that both constitutive and agonist-dependent GHSR1a activity elicit a strong impairment of CaV2.1 and CaV2.2 currents in rat and mouse hypothalamic neurons and in a heterologous expression system. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/o-dependent mechanism that involves persistent reduction in channel density at the plasma membrane, whereas ghrelin-dependent GHSR1a inhibition is reversible and involves altered CaV2 gating via a Gq-dependent pathway. Thus, GHSR1a differentially inhibits CaV2 channels by Gi/o or Gq protein pathways depending on its mode of activation. Moreover, we present evidence suggesting that GHSR1a-mediated inhibition of CaV2 attenuates GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation through the disinhibition of postsynaptic neurons. © 2015 López Soto et al.
    The Journal of General Physiology 08/2015; 146(3). DOI:10.1085/jgp.201511383 · 4.79 Impact Factor
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    • "Ghrelin is also produced in small amounts by other organs like heart, lung, lymphatic tissue, kidney, adrenal glands, thyroid gland, pancreas, gonads, some neoplastic tissues and cancer-cell lines [16] [17] [18]. Ghrelin-immunoreactive neurons are present in few regions of the brain like the arcuate and the ventromedial nucleus of the hypothalamus, cerebellum and brainstem [13] [19] [20] [21]. Ghrelin is also present in placenta along GH, GHRH, somatostatin and insulin-like growth factor 1 (IGF1) which shows that it is also involved in fetal growth [22]. "
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    ABSTRACT: Abstract Background: Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of growth hormone (GH). It is a first hormone linking gastrointestinal-pituitary axis. Objective: This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Observation: Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS–GHS receptor signalling system in the regulation of GH secretion. Conclusion: Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH. Keywords : Ghrelin, Growth Hormone, Ghrelin-Pituitary-Gh Axis Linkage System
    Journal of Clinical and Diagnostic Research 08/2014; 8(8):MC13-MC-17. DOI:10.7860/JCDR/2014/9863.4767 · 0.23 Impact Factor
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