Journal article
De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin.
- Martinetz S Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
- Meinung CP Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
- Jurek B Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
- von Schack D Biotherapeutics Clinical Research and Development, Precision Medicine, New York, New York.
- van den Burg EH Centre de Neurosciences Psychiatriques, CHUV, Lausanne, Switzerland.
- Slattery DA Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt am Main, Germany.
- Neumann ID Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany. Electronic address: inga.neumann@biologie.uni-regensburg.de.
- 2019-03-04
Published in:
- Biological psychiatry. - 2019
Anxiety
De novo protein synthesis
NPY5R
Oxytocin
PVN
eEF2
Animals
Anti-Anxiety Agents
Anxiety
Cells, Cultured
Down-Regulation
Eukaryotic Initiation Factor-2
MAP Kinase Signaling System
Male
Oxytocin
Paraventricular Hypothalamic Nucleus
Protein Kinase C
Rats, Wistar
Receptors, Neuropeptide Y
Up-Regulation
English
BACKGROUND
The neuropeptide oxytocin (OXT) mediates its actions, including anxiolysis, via its G protein-coupled OXT receptor. Within the paraventricular nucleus of the hypothalamus (PVN), OXT-induced anxiolysis is mediated, at least in part, via activation of the mitogen-activated protein kinase pathway following calcium influx through transient receptor potential cation channel subfamily V member 2 channels. In the periphery, OXT activates eukaryotic elongation factor 2 (eEF2), an essential mediator of protein synthesis.
METHODS
In order to study whether OXT activates eEF2 also in neurons to exert its anxiolytic properties in the PVN, we performed in vivo and cell culture experiments.
RESULTS
We demonstrate that OXT, in a protein kinase C-dependent manner, activates eEF2 both in a hypothalamic cell line and in vivo within the PVN. Next, we reveal that OXT stimulates de novo protein synthesis, while inhibition of protein synthesis within the PVN prevents the anxiolytic effect of OXT in male rats. Moreover, activation of eEF2 within the PVN conveyed an anxiolytic effect supporting a role of OXT-induced eEF2 activation and protein synthesis for its anxiolysis. Finally, we show that one of the proteins that is upregulated by OXT is the neuropeptide Y receptor 5. Infusion of a specific neuropeptide Y receptor 5 agonist into the PVN consequently led to decreased anxiety-related behavior, while pretreatment with a neuropeptide Y receptor 5 antagonist prevented the anxiolytic effect of OXT.
CONCLUSIONS
Taken together, these results show that OXT recruits several intracellular signaling cascades to induce protein synthesis, which mediates the anxiolytic effects of OXT within the PVN and suggests that eEF2 represents a novel target for anxiety-related disorders.
The neuropeptide oxytocin (OXT) mediates its actions, including anxiolysis, via its G protein-coupled OXT receptor. Within the paraventricular nucleus of the hypothalamus (PVN), OXT-induced anxiolysis is mediated, at least in part, via activation of the mitogen-activated protein kinase pathway following calcium influx through transient receptor potential cation channel subfamily V member 2 channels. In the periphery, OXT activates eukaryotic elongation factor 2 (eEF2), an essential mediator of protein synthesis.
METHODS
In order to study whether OXT activates eEF2 also in neurons to exert its anxiolytic properties in the PVN, we performed in vivo and cell culture experiments.
RESULTS
We demonstrate that OXT, in a protein kinase C-dependent manner, activates eEF2 both in a hypothalamic cell line and in vivo within the PVN. Next, we reveal that OXT stimulates de novo protein synthesis, while inhibition of protein synthesis within the PVN prevents the anxiolytic effect of OXT in male rats. Moreover, activation of eEF2 within the PVN conveyed an anxiolytic effect supporting a role of OXT-induced eEF2 activation and protein synthesis for its anxiolysis. Finally, we show that one of the proteins that is upregulated by OXT is the neuropeptide Y receptor 5. Infusion of a specific neuropeptide Y receptor 5 agonist into the PVN consequently led to decreased anxiety-related behavior, while pretreatment with a neuropeptide Y receptor 5 antagonist prevented the anxiolytic effect of OXT.
CONCLUSIONS
Taken together, these results show that OXT recruits several intracellular signaling cascades to induce protein synthesis, which mediates the anxiolytic effects of OXT within the PVN and suggests that eEF2 represents a novel target for anxiety-related disorders.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1016/j.biopsych.2019.01.010
- PMID 30826070
- Persistent URL
- https://sonar.ch/global/documents/663
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