NMDA-induced nitric oxide generation and CREB activation in central nervous system is dependent on eukaryotic elongation factor 2 kinase

Gladulich, Luis Felipe Homem; Peixoto-Rodrigues, Maria Carolina; Campello-Costa, Paula; Paes‐de‐Carvalho, Roberto; Cossenza, Marcelo

doi:10.1016/j.bbamcr.2020.118783

Cited by 7 publications

(12 citation statements)

References 41 publications

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“…eEF2K activity and inhibition of protein synthesis have previously been linked with correct synaptic maintenance and survival, especially during events related to neuronal plasticity (Cossenza et al., 2020; Gladulich, Peixoto‐Rodrigues, Campello‐Costa, Paes‐de‐Carvalho, & Cossenza, 2020; Heise et al., 2014; Proud, 2015). The expression of a specific set of proteins is, paradoxically, increased upon eEF2K activation; these include the α‐subunit of CaMKII; BDNF; Arc/Arg3.1 and MAPB1 (Davidkova & Carroll, 2007; Park et al., 2008; Scheetz et al., 2000; Verpelli et al., 2010).…”

Section: Discussionmentioning

confidence: 99%

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

Gladulich

Xie

Jensen

et al. 2020

Journal of Neurochemistry

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The regulation of protein synthesis is a vital and finely tuned process in cellular physiology. In neurons, this process is very precisely regulated, as which mRNAs undergo translation is highly dependent on context. One of the most prominent regulators of protein synthesis is the enzyme eukaryotic elongation factor kinase 2 (eEF2K) that regulates the elongation stage of protein synthesis. This kinase and its substrate, eukaryotic elongation factor 2 (eEF2) are important in processes such as neuronal development and synaptic plasticity. eEF2K is regulated by multiple mechanisms including Ca 2+ -ions and the mTORC1 signaling pathway, both of which play key roles in neurological processes such as learning and memory. In such settings, the localized control of protein synthesis is of crucial importance. In this work, we sought to investigate how the localization of eEF2K is controlled and the impact of this on protein synthesis in neuronal cells. In this study, we used both SH-SY5Y neuroblastoma cells and mouse cortical neurons, and pharmacologically and/or genetic approaches to modify eEF2K function. We show that eEF2K activity and localization can be regulated by its binding partner Homer1b/c, a scaffolding protein known for its participation in calcium-regulated signaling pathways. Furthermore, our results indicate that this interaction is regulated by the mTORC1 pathway, through a known phosphorylation site in eEF2K (S396), and that it affects rates of localized protein synthesis at synapses depending on the presence or absence of this scaffolding protein.

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Section: Discussionmentioning

confidence: 99%

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

Gladulich

Xie

Jensen

et al. 2020

Journal of Neurochemistry

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“…NMDAR stimulation activates the enzyme calcium calmodulin kinase III (CaMKIII) [36,37], currently known as eukaryotic elongation factor 2 kinase (eEF2K), due to the recognition that its only activity is the phosphorylation of Thr-56 of the translation factor eEF2 [38][39][40]. eEF2 mediates the translocation of peptidyl-tRNA from the ribosomal A-site to P-site by GTP hydrolysis, consuming a significant amount of energy.…”

Section: Glutamatementioning

confidence: 99%

“…It has been reported that the expression of some synaptic proteins, such as the alpha subunit of CaMKII in isolated synaptosomes [46] and brain-derived neurotrophic factor (BDNF) [47], paradoxically increases with NMDAR/Ca 2+ -CaM/eEF2K activation, despite this pathway inhibiting general protein synthesis, an effect that is not yet completely understood. The activation of the NMDAR/Ca 2+ -CaM/eEF2K pathway was described to enhance the availability of intracellular free L-arginine, contributing to increased NO synthesis by nNOS [36,37]. Therefore, NMDA-triggered Ca 2+ signaling could operate in two different ways to increase NO production: (1) by activating nNOS directly; and (2) by supplying the nNOS substrate, L-Arg.…”

Section: Glutamatementioning

confidence: 99%

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

Tempone,

Borges-Martins,

César

et al. 2024

IJMS

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The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.

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“…Interestingly, NMDA receptors also not only modulate NO production but protein synthesis in chick retina cells (Cossenza and Paes-de-Carvalho, 2000;Cossenza et al, 2006Cossenza et al, , 2014Gladulich et al, 2020). Stimulation of NMDA receptors activates the Ca 2+ /calmodulin-dependent enzyme eEF2K, a kinase that phosphorylates the elongation factor eEF2 and inhibit its activity, promoting a decrease of protein synthesis rate (Cossenza and Paes-de-Carvalho, 2000;Cossenza et al, 2006Cossenza et al, , 2014Gladulich et al, 2020). Experiments utilizing arginine-free solutions demonstrated that inhibition of eEF2K also promotes an increase of NMDA-dependent NO production (Gladulich et al, 2020).…”

Section: Glutamate In the Retinamentioning

confidence: 99%

“…Stimulation of NMDA receptors activates the Ca 2+ /calmodulin-dependent enzyme eEF2K, a kinase that phosphorylates the elongation factor eEF2 and inhibit its activity, promoting a decrease of protein synthesis rate (Cossenza and Paes-de-Carvalho, 2000;Cossenza et al, 2006Cossenza et al, , 2014Gladulich et al, 2020). Experiments utilizing arginine-free solutions demonstrated that inhibition of eEF2K also promotes an increase of NMDA-dependent NO production (Gladulich et al, 2020). This effect would be due to an increase of arginine availability for NO production since this amino acid would be less directed towards protein synthesis.…”

Section: Glutamate In the Retinamentioning

confidence: 99%

Chemical signaling in the developing avian retina: Focus on cyclic AMP and AKT-dependent pathways

Duarte-Silva

Ximenes

Guimarães-Souza

et al. 2022

Front. Cell Dev. Biol.

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Communication between developing progenitor cells as well as differentiated neurons and glial cells in the nervous system is made through direct cell contacts and chemical signaling mediated by different molecules. Several of these substances are synthesized and released by developing cells and play roles since early stages of Central Nervous System development. The chicken retina is a very suitable model for neurochemical studies, including the study of regulation of signaling pathways during development. Among advantages of the model are its very well-known histogenesis, the presence of most neurotransmitter systems found in the brain and the possibility to make cultures of neurons and/or glial cells where many neurochemical functions develop in a similar way than in the intact embryonic tissue. In the chicken retina, some neurotransmitters or neuromodulators as dopamine, adenosine, and others are coupled to cyclic AMP production or adenylyl cyclase inhibition since early stages of development. Other substances as vitamin C and nitric oxide are linked to the major neurotransmitter glutamate and AKT metabolism. All these different systems regulate signaling pathways, including PKA, PKG, SRC, AKT and ERK, and the activation of the transcription factor CREB. Dopamine and adenosine stimulate cAMP accumulation in the chick embryo retina through activation of D1 and A2a receptors, respectively, but the onset of dopamine stimulation is much earlier than that of adenosine. However, adenosine can inhibit adenylyl cyclase and modulate dopamine-dependent cAMP increase since early developmental stages through A1 receptors. Dopamine stimulates different PKA as well as EPAC downstream pathways both in intact tissue and in culture as the CSK-SRC pathway modulating glutamate NMDA receptors as well as vitamin C release and CREB phosphorylation. By the other hand, glutamate modulates nitric oxide production and AKT activation in cultured retinal cells and this pathway controls neuronal survival in retina. Glutamate and adenosine stimulate the release of vitamin C and this vitamin regulates the transport of glutamate, activation of NMDA receptors and AKT phosphorylation in cultured retinal cells. In the present review we will focus on these reciprocal interactions between neurotransmitters or neuromodulators and different signaling pathways during retinal development.

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NMDA-induced nitric oxide generation and CREB activation in central nervous system is dependent on eukaryotic elongation factor 2 kinase

Cited by 7 publications

References 41 publications

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

Chemical signaling in the developing avian retina: Focus on cyclic AMP and AKT-dependent pathways

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