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De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin.

Abstract：

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.

journal_name

Biol Psychiatry

journal_title

Biological psychiatry

authors

Martinetz S,Meinung CP,Jurek B,von Schack D,van den Burg EH,Slattery DA,Neumann ID

doi

10.1016/j.biopsych.2019.01.010

subject

Has Abstract

pub_date

2019-05-15 00:00:00

pages

802-811

issue

eissn

0006-3223

issn

1873-2402

pii

S0006-3223(19)30036-8

journal_volume

pub_type

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De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin.