title: Inhibition of food intake by PACAP in the hypothalamic ventromedial nuclei is mediated by NMDA receptors.
abstract: Central injections of pituitary adenylate cyclase-activating polypeptide (PACAP) into the ventromedial nuclei (VMN) of the hypothalamus produce hypophagia that is dependent upon the PAC1 receptor; however, the signaling downstream of this receptor in the VMN is unknown. Though PACAP signaling has many targets, this neuropeptide has been shown to influence glutamate signaling in several brain regions through mechanisms involving NMDA receptor potentiation via activation of the Src family of protein tyrosine kinases. With this in mind, we examined the Src-NMDA receptor signaling pathway as a target for PACAP signaling in the VMN that may mediate its effects on feeding behavior. Under nocturnal feeding conditions, NMDA receptor antagonism prior to PACAP administration into the VMN attenuated PACAP-mediated decreases in feeding suggesting that glutamatergic signaling via NMDA receptors is necessary for PACAP-induced hypophagia. Furthermore, PACAP administration into the VMN resulted in increased tyrosine phosphorylation of the GluN2B subunit of the NMDA receptor, and inhibition of Src kinase activity also blocked the effects of PACAP administration into the VMN on feeding behavior. These results indicate that PACAP neurotransmission in the VMN likely augments glutamate signaling by potentiating NMDA receptors activity through the tyrosine phosphorylation events mediated by the Src kinase family, and modulation of NMDA receptor activity by PACAP in the hypothalamus may be a primary mechanism for its regulation of food intake.
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Resch
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Maunze
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA.
authors.forename: Kailynn A
authors.initials: KA
authors.lastname: Phillips
authors.affiliation: Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA. Electronic address: sujean.choi@marquette.edu.
authors.forename: SuJean
authors.initials: S
authors.lastname: Choi
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins; D004435:Eating / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009687:Nuclear Proteins; D010766:Phosphorylation / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D029681:Arabidopsis Proteins; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016194:Receptors, N-Methyl-D-Aspartate; C523534:TIC protein, Arabidopsis; D014443:Tyrosine; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine
keywords: Feeding; Glutamate; PACAP; Src kinase; VMN