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

Martinetz, Stefanie; Meinung, Carl-Philipp; Jurek, Benjamin; Schack, David von; Burg, Erwin H. van den; Slattery, David A.; Neumann, Inga D.

doi:10.1016/j.biopsych.2019.01.010

Cited by 20 publications

(24 citation statements)

References 58 publications

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“…The MAPK pathway has been associated with OT-induced anxiolysis, i.e. reduction of anxiety-like behavior in rats (Blume et al, 2008;Jurek et al, 2015;Jurek et al, 2012;Martinetz et al, 2019; and targets transcription factors like CREB and its cofactor CRTC3 (Jurek et al, 2015;Tomizawa et al, 2003). The MAPK pathway is certainly one of the main effectors of OTR signaling (Jurek and Neumann, 2018); however, it might not be directly linked to MEF2A activation, mainly because the S408 residue requires dephosphorylation, not phosphorylation, for full transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence of neurite outgrowth, altered connectivity is observable due to increased synapse formation, which is under the OT-induced control of synaptic adhesion molecules like neuroligin 3 or neurexin 2 (Zatkova et al, 2019). Since OT is produced in the hypothalamus and we have found profound anxiolytic and anti-stress effects of OT infused into the hypothalamic paraventricular nucleus (Blume et al, 2008;Jurek et al, 2015;Jurek et al, 2012;Martinetz et al, 2019), we aimed to determine the intracellular effects of OT in a hypothalamic cell line, as opposed to neuroblastoma or glioblastoma cell types. As a cellular model of OTergic effects, we have characterized the rat hypothalamic neuronal cell line H32, which expresses MEF2A endogenously, and retract their neurites upon OT stimulation, caused by MEF2A activation (Meyer et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

Meyer¹,

Kuffner²,

Winter³

et al. 2020

Preprint

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The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair-bonding, however, when dysregulated, it is associated with adverse psychiatric traits, like various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor MEF2A as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare-respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

Meyer¹,

Kuffner²,

Winter³

et al. 2020

Preprint

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“…On a molecular level, upon activation, the G protein-coupled OXT receptor (OXTR) mediates its behavioral effects by multiple intraneuronal signaling cascades (Busnelli and Chini, 2018;Jurek and Neumann, 2018). In brief, the G protein αq subunit is at the basis of activation of protein kinase C (PKC) (Martinetz et al, 2019), whereas the β/γ subunit activates Ca 2+ -influx through transient receptor potential vanilloid type 2 (TRPV2) channels . PKC and Ca 2+ transactivate the epidermal growth factor receptor (Blume et al, 2008), which is followed by the recruitment of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) signaling and protein synthesis (Martinetz et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…In brief, the G protein αq subunit is at the basis of activation of protein kinase C (PKC) (Martinetz et al, 2019), whereas the β/γ subunit activates Ca 2+ -influx through transient receptor potential vanilloid type 2 (TRPV2) channels . PKC and Ca 2+ transactivate the epidermal growth factor receptor (Blume et al, 2008), which is followed by the recruitment of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) signaling and protein synthesis (Martinetz et al, 2019). Both MEK1/2 signaling and protein synthesis are necessary for the acute anxiolytic effect of OXT in the PVN of male (Blume et al, 2008;Martinetz et al, 2019) and virgin female (Jurek et al, 2012) rats.…”

Section: Introductionmentioning

confidence: 99%

“…PKC and Ca 2+ transactivate the epidermal growth factor receptor (Blume et al, 2008), which is followed by the recruitment of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) signaling and protein synthesis (Martinetz et al, 2019). Both MEK1/2 signaling and protein synthesis are necessary for the acute anxiolytic effect of OXT in the PVN of male (Blume et al, 2008;Martinetz et al, 2019) and virgin female (Jurek et al, 2012) rats. The anxiolytic activity of OXT in the PVN might be enhanced under mild stress conditions (Blume et al, 2008), indicating an interaction of OXT with central stress regulation.…”

Section: Introductionmentioning

confidence: 99%

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Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety

Winter

Meyer

Berger

et al. 2020

Preprint

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Recently, oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including general anxiety disorder or autism spectrum disorder. Therefore, knowledge on the involved molecular processes downstream of OXT receptor (OXTR) activation is indispensable. We reveal that alternative splicing of corticotropin releasing factor receptor 2a (CRFR2a) parallels increased anxiety-like behavior following chronic OXT treatment, contrasting the well-known anxiolysis of acute OXT. In detail, chronic OXT shifts the splicing ratio between membrane-bound (mCRFR2a) and soluble CRFR2a (sCRFR2a) in favor of the latter via ERK1/2-MEF2A signaling. Targeted manipulations of Crfr2a splicing mimic the effect of chronic OXT, confirming its role in the regulation of anxiety-like behavior. Furthermore, chronic OXT triggers cytoplasmic distribution and extracellular release of sCRFR2a into the cerebrospinal fluid, with sCRFR2a levels positively correlating with anxiety-like behavior. Concluding, the dichotomy between anxiolytic mCRFR2a and anxiogenic sCRFR2a is the basis for the deleterious effects of chronic OXT on anxiety.

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Ghrelin rapidly elevates protein synthesis in vitro by employing the rpS6K-eEF2K-eEF2 signalling axis

Zhdanov

Golubeva

Yordanova

et al. 2022

Cell. Mol. Life Sci.

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Activated ghrelin receptor GHS-R1α triggers cell signalling pathways that modulate energy homeostasis and biosynthetic processes. However, the effects of ghrelin on mRNA translation are unknown. Using various reporter assays, here we demonstrate a rapid elevation of protein synthesis in cells within 15–30 min upon stimulation of GHS-R1α by ghrelin. We further show that ghrelin-induced activation of translation is mediated, at least in part, through the de-phosphorylation (de-suppression) of elongation factor 2 (eEF2). The levels of eEF2 phosphorylation at Thr56 decrease due to the reduced activity of eEF2 kinase, which is inhibited via Ser366 phosphorylation by rpS6 kinases. Being stress-susceptible, the ghrelin-mediated decrease in eEF2 phosphorylation can be abolished by glucose deprivation and mitochondrial uncoupling. We believe that the observed burst of translation benefits rapid restocking of neuropeptides, which are released upon GHS-R1α activation, and represents the most time- and energy-efficient way of prompt recharging the orexigenic neuronal circuitry.

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

Cited by 20 publications

References 58 publications

Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

Chronic oxytocin-driven alternative splicing of CRFR2α induces anxiety

Ghrelin rapidly elevates protein synthesis in vitro by employing the rpS6K-eEF2K-eEF2 signalling axis

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