title: Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats.
abstract: Vagal afferent nerve fibers transmit gastrointestinal satiation signals to the brain via synapses in the nucleus of the solitary tract (NTS). Despite their pivotal role in energy homeostasis, little is known about the cellular mechanisms enabling fleeting synaptic events at vagal sensory endings to sustain behavioral changes lasting minutes to hours. Previous reports suggest that the reduction of food intake by the satiation peptide, cholecystokinin (CCK), requires activation of N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the NTS, with subsequent phosphorylation of ERK1/2 (pERK1/2) in NTS vagal afferent terminals. The synaptic vesicle protein synapsin I is phosphorylated by pERK1/2 at serines 62 and 67. This pERK1/2-catalyzed phosphorylation increases synaptic strength by increasing the readily releasable pool of the neurotransmitter. Conversely, dephosphorylation of serines 62 and 67 by calcineurin reduces the size of the readily releasable transmitter pool. Hence, the balance of synapsin I phosphorylation and dephosphorylation can modulate synaptic strength. We postulated that CCK-evoked activation of vagal afferent NMDARs results in pERK1/2-catalyzed phosphorylation of synapsin I in vagal afferent terminals, leading to the suppression of food intake. We found that CCK injection increased the phosphorylation of synapsin I in the NTS and that this increase is abolished after surgical or chemical ablation of vagal afferent fibers. Furthermore, fourth ventricle injection of an NMDAR antagonist or the mitogen-activated ERK kinase inhibitor blocked CCK-induced synapsin I phosphorylation, indicating that synapsin phosphorylation in vagal afferent terminals depends on NMDAR activation and ERK1/2 phosphorylation. Finally, hindbrain inhibition of calcineurin enhanced and prolonged synapsin I phosphorylation and potentiated reduction of food intake by CCK. Our findings are consistent with a mechanism in which NMDAR-dependent phosphorylation of ERK1/2 modulates satiation signals via synapsin I phosphorylation in vagal afferent endings.
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA. carloscampos@vetmed.wsu.edu
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Campos
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shiina
authors.forename: Michael
authors.initials: M
authors.lastname: Silvas
authors.forename: Stephen
authors.initials: S
authors.lastname: Page
authors.forename: Robert C
authors.initials: RC
authors.lastname: Ritter
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012527:Satiation / Q000187:drug effects / Q000502:physiology; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016704:Synapsins / Q000378:metabolism*; D014630:Vagus Nerve / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009570:Nitriles; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D016704:Synapsins; C113580:U 0126; C065286:SDZ EAA 494; D002766:Cholecystokinin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3