title: Lateral hypothalamic signaling mechanisms underlying feeding stimulation: differential contributions of Src family tyrosine kinases to feeding triggered either by NMDA injection or by food deprivation.
abstract: In rats, feeding can be triggered experimentally using many approaches. Included among these are (1) food deprivation and (2) acute microinjection of the neurotransmitter l-glutamate (Glu) or its receptor agonist NMDA into the lateral hypothalamic area (LHA). Under both paradigms, the NMDA receptor (NMDA-R) within the LHA appears critically involved in transferring signals encoded by Glu to stimulate feeding. However, the intracellular mechanisms underlying this signal transfer are unknown. Because protein-tyrosine kinases (PTKs) participate in NMDA-R signaling mechanisms, we determined PTK involvement in LHA mechanisms underlying both types of feeding stimulation through food intake and biochemical measurements. LHA injections of PTK inhibitors significantly suppressed feeding elicited by LHA NMDA injection (up to 69%) but only mildly suppressed deprivation feeding (24%), suggesting that PTKs may be less critical for signals underlying this feeding behavior. Conversely, food deprivation but not NMDA injection produced marked increases in apparent activity for Src PTKs and in the expression of Pyk2, an Src-activating PTK. When considered together, the behavioral and biochemical results demonstrate that, although it is easier to suppress NMDA-elicited feeding by PTK inhibitors, food deprivation readily drives PTK activity in vivo. The latter result may reflect greater PTK recruitment by neurotransmitter receptors, distinct from the NMDA-R, that are activated during deprivation-elicited but not NMDA-elicited feeding. These results also demonstrate how the use of only one feeding stimulation paradigm may fail to reveal the true contributions of signaling molecules to pathways underlying feeding behavior in vivo.
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, USA. arshadk@usc.edu
authors.forename: Arshad M
authors.initials: AM
authors.lastname: Khan
authors.forename: Herman H
authors.initials: HH
authors.lastname: Cheung
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gillard
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Palarca
authors.forename: Derek S
authors.initials: DS
authors.lastname: Welsbie
authors.forename: James W
authors.initials: JW
authors.lastname: Gurd
authors.forename: B Glenn
authors.initials: BG
authors.lastname: Stanley
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D051418:Focal Adhesion Kinase 2; D005508:Food Deprivation / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000201:enzymology / Q000502:physiology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: C501731:2-amino-4-(4'-hydroxyphenyl)-1,1,3-tricyanobuta-1,3-diene; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D002070:Butadienes; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D019061:src-Family Kinases; D007608:Kainic Acid