Journal of neurochemistry
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Journal of neurochemistry · Nov 2015
Adenosine A₂A receptors permit mGluR5-evoked tyrosine phosphorylation of NR2B (Tyr1472) in rat hippocampus: a possible key mechanism in NMDA receptor modulation.
A great body of evidence points toward a functional interaction between metabotropic glutamate 5 receptors (mGluR5) and NMDA receptors (NMDAR) that enhances synaptic plasticity and cognition. However, the molecular mechanism underlying this interaction remains unclear. Here, we show that co-activation of mGluR5 and NMDAR in hippocampal slices synergistically leads to a robust phosphorylation of NR2B (Tyr1472), which is Src kinase dependent and is enabled by endogenous adenosine acting on A2A receptors. ⋯ We propose the following molecular mechanism by which metabotropic Glutamate Receptor 5 (mGluR5) potentiate ionotropic Glutamate N-Methyl-D-Aspartate Receptor (NMDAR) responses in rat hippocampus. Co-activation of mGLUR5/NMDAR activates Src kinases, leading to NR2B(Tyr1472) phosphorylation, which anchors NR2B-containing NMDAR to the plasma membrane, thus inducing a robust increase in the NMDA-dependent excitability. Interestingly, adenosine A2A receptors license the mGluR5-induced NR2B(Tyr1472) phosphorylation.
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Journal of neurochemistry · Nov 2015
Editorial CommentAn integrated energy plan for activated neurons.
This Editorial highlights an ingenious study by Li and Freeman published in this issue of J. Neurochem. ⋯ To that end, the authors have designed a new approach that consists to record at the same time (100 ms resolution) extracellular glucose and lactate concentrations using electrochemical sensing microelectrodes equally distant from a microelectrode that registers the multicellular activity in response to light-dependent stimuli (contrast levels from 10% to 80%). While this approach does, however, not evaluate the metabolic coupling between astrocytes and neurons, it proposes a new design which combined with molecular strategies specifically toward the glial or neuronal compartments will certainly help to demonstrate new distinctive features of this interesting question.
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Journal of neurochemistry · Nov 2015
Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats.
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase (AC) and protein kinase A (PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. ⋯ Calcitonin gene-related peptide (CGRP) plays an essential role in synaptic plasticity in the amygdala and fear memory. We found that CGRP-induced chemical long-term potentiation (LTP) in a dose-dependent way in the BLA-CeA (basolateral and central nucleus of amygdala, respectively) pathway and enhanced fear memory extinction in rats through a protein kinase A (PKA)-dependent postsynaptic mechanism that involved NMDA receptors. These results support a pivotal role of CGRP in amygdala.
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Journal of neurochemistry · Oct 2015
Mu opioid receptor activation enhances regulator of G protein signaling 4 association with the mu opioid receptor/G protein complex in a GTP-dependent manner.
The interaction of Regulator of G protein Signaling 4 (RGS4) with the rat mu opioid receptor (MOR)/G protein complex was investigated. Solubilized MOR from rat brain membranes was immunoprecipitated in the presence of RGS4 with antibodies against the N-terminus of MOR (anti-MOR10-70 ). Activation of MOR with [D-Ala(2) , N-Me-Phe(4) , Gly(5) -ol] enkephalin (DAMGO) during immunoprecipitation caused a 150% increase in Goα and a 50% increase in RGS4 in the pellet. ⋯ Activation of the mu opioid receptor (MOR) causes GTP to bind to and to activate Go (αoβγ). RGS4 then binds to the activated αo-GTP/MOR complex and accelerates the intrinsic GTPase of αo. After αo dissociates from MOR, RGS4 remains bound to the C-terminal region of MOR.
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Journal of neurochemistry · Oct 2015
The mitochondrial uncoupling protein-2 is a master regulator of both M1 and M2 microglial responses.
Microglial activation is a dynamic process, central to neuroinflammation, which can have beneficial or pathogenic effects to human health. Mitochondria are key players in neuroinflammatory and neurodegenerative processes, common to most brain diseases. To the best of our knowledge on the role of mitochondria in the modulation of neuroinflammation, we focused on the mitochondrial uncoupling protein-2 (UCP2), known to control mitochondrial functions and to be implicated in a variety of physiological and pathological processes. ⋯ We show that the mitochondrial uncoupling protein-2 (UCP2) is central to the process of microglial activation, with opposite regulation of M1 and M2 responses. In UCP2-silenced microglia, lipopolysaccharide (LPS) triggers an enhanced inflammatory response characterized by a greater expression of M1 genes, whereas interleukin-4 (IL-4) fails in inducing M2 genes and reducing M1 genes. We propose UCP2 manipulation as a potential strategy for redirecting microglial response towards protective phenotypes.