title: Ghrelin and obestatin modulate growth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons.
abstract: Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.
authors.affiliation: INSERM UMR 894, Psychiatry and Neurosciences Center, 2ter rue d'Alésia, 75014 Paris, France.
authors.forename: Dan D
authors.initials: DD
authors.lastname: Feng
authors.forename: Seung-Kwon
authors.initials: SK
authors.lastname: Yang
authors.forename: Catherine
authors.initials: C
authors.lastname: Loudes
authors.forename: Axelle
authors.initials: A
authors.lastname: Simon
authors.forename: Tamara
authors.initials: T
authors.lastname: Al-Sarraf
authors.forename: Michael
authors.initials: M
authors.lastname: Culler
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Alvear-Perez
authors.forename: Catherine
authors.initials: C
authors.lastname: Llorens-Cortes
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Jacques
authors.initials: J
authors.lastname: Epelbaum
authors.forename: Robert
authors.initials: R
authors.lastname: Gardette
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D054439:Ghrelin / Q000378:metabolism / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D036361:Peptide Hormones / Q000494:pharmacology; D054440:Receptors, Ghrelin / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C492347:BIM28163; D058787:GABA-A Receptor Antagonists; D054439:Ghrelin; D036361:Peptide Hormones; D054440:Receptors, Ghrelin; D018698:Glutamic Acid; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D013007:Growth Hormone-Releasing Hormone; D001640:Bicuculline