title: Ghrelin-induced activation of cAMP signal transduction and its negative regulation by endocannabinoids in the hippocampus.
abstract: Increasing evidence indicates that the gut peptide ghrelin facilitates learning behavior and memory tasks. The present study demonstrates a cellular signaling mechanism of ghrelin in the hippocampus. Ghrelin stimulated CREB (cAMP response-element binding protein) through the activation of cAMP, protein kinase A (PKA), and PKA-dependent phosphorylation of NR1 subunit of the NMDA receptor. Ghrelin increased phalloidin-binding to F-actin suggesting CREB-induced gene expression might include reorganization of cytoskeletal proteins. The effect was blocked by the antagonist of the ghrelin receptor in spite of the receptor's primary coupling to Gq proteins. We also discovered inhibitory effect of endocannabinoids on ghrelin-induced NR1 phosphorylation and CREB activity. 2-arachidonoylglycerol (2-AG) exerted its inhibitory effect in the Type 1 cannabinoid receptor (CB1R)-dependent manner, while anandamide's inhibitory effect persisted in the presence of antagonists of CB1R and the vanilloid receptor, suggesting that anandamide might directly inhibit NMDA receptor/channels. Our findings may explain how ghrelin and endocannabinoids regulate hippocampal appetitive learning and plasticity.
authors.affiliation: Department of Biological Sciences, The University of Texas at Brownsville, 80 Fort Brown, Brownsville, TX 78520, USA.
authors.forename: Jacquelynn N
authors.initials: JN
authors.lastname: Cuellar
authors.forename: Masako
authors.initials: M
authors.lastname: Isokawa
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology / Q000502:physiology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D063388:Endocannabinoids; D005786:Gene Expression Regulation / Q000187:drug effects*; D054439:Ghrelin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D010590:Phalloidine / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D000199:Actins; D063385:Cannabinoid Receptor Modulators; D017362:Cyclic AMP Response Element-Binding Protein; D063388:Endocannabinoids; D054439:Ghrelin; C409466:NR1 NMDA receptor; D043884:Receptor, Cannabinoid, CB1; D016194:Receptors, N-Methyl-D-Aspartate; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013873:Thionucleotides; D010590:Phalloidine; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP