scholarly journals ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity

2018 ◽  
Author(s):  
Sonam Gurung ◽  
Ashley J. Evans ◽  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Neuronal Excitability ◽  
Proteasomal Degradation ◽  
Surface Expression ◽  
Synaptic Activity ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Mrna Editing ◽  
Network Function ◽  
Ampar Trafficking ◽  
Editing Enzyme

AbstractKainate receptors (KARs) regulate neuronal excitability and network function. Most KARs contain the subunit GluK2 and the properties of these receptors are determined in part by ADAR2-mediated mRNA editing of GluK2 that changes a genomically encoded glutamine (Q) to arginine (R). Suppression of synaptic activity reduces ADAR2-dependent Q/R editing of GluK2 with a consequential increase in GluK2-containing KAR surface expression. However, the mechanism underlying this reduction in GluK2 editing has not been addressed. Here we show that induction of KAR upscaling results in proteasomal degradation of ADAR2, which reduces GluK2 Q/R editing. Because KARs incorporating unedited GluK2(Q) assemble and exit the ER more efficiently this leads to an upscaling of KAR surface expression. Consistent with this, we demonstrate that partial ADAR2 knockdown phenocopies and occludes KAR upscaling. Moreover, we show that although the AMPAR subunit GluA2 also undergoes ADAR2-dependent Q/R editing, this process does not mediate AMPAR upscaling. These data demonstrate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing are key determinants of KAR, but not AMPAR, trafficking and upscaling.Summary statementSynaptic suppression promotes proteasomal degradation of the mRNA-editing enzyme ADAR2. Decreased ADAR2 levels reduce Q/R editing of the kainate receptor subunit GluK2 leading to enhanced surface expression and homeostatic upscaling.

scholarly journals ADAR2 mediated Q/R editing of GluK2 regulates homeostatic plasticity of kainate receptors

2018 ◽  
Author(s):  
Sonam Gurung ◽  
Ashley J. Evans ◽  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Neuronal Excitability ◽  
Surface Expression ◽  
Synaptic Activity ◽  
Homeostatic Plasticity ◽  
Kainate Receptors ◽  
Mrna Editing ◽  
Network Function ◽  
Pore Lining ◽  
Activity Dependent ◽  
The Brain

AbstractKainate receptors (KARs) are heteromeric glutamate-gated ion channels that regulate neuronal excitability and network function in the brain. Most KARs contain the subunit GluK2 and the precise properties of these GluK2-containing KARs are determined by additional factors including ADAR2-mediated mRNA editing of a single codon that changes a genomically encoded glutamine (Q) to arginine (R) in the pore-lining region of GluK2. ADAR2-dependent Q/R editing of GluK2 is dynamically regulated during homeostatic plasticity (scaling) elicited by suppression of synaptic activity with TTX. Here we show that TTX decreases levels of ADAR2 by enhancing its proteasomal degradation. This selectively reduces the numbers of GluK2 subunits that are edited and increases the surface expression of GluK2-containing KARs. Furthermore, we show that partial ADAR2 knockdown phenocopies and occludes TTX-induced scaling of KARs. These data indicate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing provides a mechanism for KAR homeostatic plasticity.

Synaptic plasticity of kainate receptors

2006 ◽  
Vol 34 (5) ◽  
pp. 949-951 ◽  
Author(s):  
J.R. Mellor
Keyword(s):  
Synaptic Plasticity ◽  
Receptor Trafficking ◽  
Synaptic Activity ◽  
Kainate Receptors ◽  
Ionotropic Glutamate Receptors ◽  
Kainate Receptor ◽  
Ionotropic Glutamate Receptor ◽  
Cellular Mechanisms ◽  
The Third ◽  
Current State

Synaptic plasticity of ionotropic glutamate receptors has been extensively studied with a particular focus on the role played by NMDA (N-methyl-D-aspartate) receptors in the induction of synaptic plasticity and the subsequent movement of AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors. The third subtype of ionotropic glutamate receptor, kainate receptors, has not been studied to the same extent, but recent evidence shows that these receptors also exhibit synaptic plasticity in response to activity. There is also a growing body of data on the mechanisms underlying kainate receptor trafficking and the proteins they interact with. This review summarizes the current state of knowledge on this topic, focusing on the evidence for the removal or insertion of functional kainate receptors in response to synaptic activity and the cellular mechanisms that underlie this regulation of neuronal kainate receptor function.

scholarly journals JNK activity modulates postsynaptic scaffold protein SAP102 and kainate receptor dynamics in dendritic spines

2021 ◽  
Author(s):  
Stella-Amrei Kunde ◽  
Bettina Schmerl ◽  
Elham Ahmadyar ◽  
Nils Rademacher ◽  
Hanna L Zieger ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Surface Expression ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Receptor Subunit ◽  
Developmental Defects ◽  
Receptor Dynamics ◽  
Regulated Trafficking ◽  
Scaffold Molecule ◽  
Shed Light

We show here that the dynamics of the synaptic scaffold molecule SAP102 are negatively regulated by JNK inhibition, that SAP102 is a direct phosphorylation target of JNK3, and that SAP102 regulation by JNK is restricted to neurons that harbour mature synapses. We further demonstrate that SAP102 and JNK3 cooperate in the regulated trafficking of kainate receptors to the cell membrane. Specifically, we observe that SAP102, JNK3, and the kainate receptor subunit GluK2 exhibit overlapping expression at synaptic sites, and that modulating JNK activity influences the surface expression of the kainate receptor subunit GluK2 in a neuronal context. We also show that SAP102 participates in this process in a JNK-dependent fashion. In summary, our data support a model in which JNK-mediated regulation of SAP102 influences the dynamic trafficking of kainate receptors to postsynaptic sites, and thus shed light on common pathophysiological mechanisms underlying the cognitive developmental defects associated with diverse mutations.

scholarly journals Mutational analysis of apolipoprotein B mRNA editing enzyme (APOBEC1): structure–function relationships of RNA editing and dimerization

1999 ◽  
Vol 40 (4) ◽  
pp. 623-635 ◽  
Author(s):  
Ba-Bie Teng ◽  
Scott Ochsner ◽  
Qian Zhang ◽  
Kizhake V. Soman ◽  
Paul P. Lau ◽  
...  
Keyword(s):  
Structure Function ◽  
Rna Editing ◽  
Apolipoprotein B ◽  
Mutational Analysis ◽  
Mrna Editing ◽  
Editing Enzyme

scholarly journals CCR6 ligands inhibit HIV by inducing APOBEC3G

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1564-1571 ◽  
Author(s):  
Mark K. Lafferty ◽  
Lingling Sun ◽  
Leon DeMasi ◽  
Wuyuan Lu ◽  
Alfredo Garzino-Demo
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Early Stage ◽  
Intrinsic Immunity ◽  
Mrna Editing ◽  
Host Restriction ◽  
Host Restriction Factor ◽  
Mechanism Of Inhibition ◽  
Editing Enzyme ◽  
Apobec3g Expression

AbstractWe have identified a postentry CCR6-dependent mechanism of inhibition of HIV occurring at an early stage of infection mediated by the induction of the host restriction factor apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G). We observed induction of APOBEC3G expression only in CCR6+ cells but not in cells treated with the G inhibitory (Gi) pathway inhibitor pertussis toxin. CCR6 is highly expressed on peripheral blood CD4+CCR5+ memory T cells and by 2 populations of CD4+ T cells within the gut, α4β7+ and T helper type 17, that have been implicated in cell-to-cell spread of HIV and enhanced restoration of CD4+ T cells within gut-associated lymphoid tissue, respectively. This novel CCR6-mediated mechanism of inhibition allows the identification of pathways that induce intrinsic immunity to HIV, which could be useful in devising novel therapeutics that selectively target CCR6+ cells.

scholarly journals Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins

2020 ◽  
Vol 8 (12) ◽  
pp. 1976
Author(s):  
Yoshiyuki Hakata ◽  
Masaaki Miyazawa
Keyword(s):  
Molecular Mechanisms ◽  
Restriction Factors ◽  
Mrna Editing ◽  
Antiviral Function ◽  
Apobec3 Proteins ◽  
And Function ◽  
Editing Enzyme ◽  
Dependent Pathway ◽  
Independent Mode ◽  
Human Apobec3g

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins (APOBEC3s) are deaminases that convert cytosines to uracils predominantly on a single-stranded DNA, and function as intrinsic restriction factors in the innate immune system to suppress replication of viruses (including retroviruses) and movement of retrotransposons. Enzymatic activity is supposed to be essential for the APOBEC3 antiviral function. However, it is not the only way that APOBEC3s exert their biological function. Since the discovery of human APOBEC3G as a restriction factor for HIV-1, the deaminase-independent mode of action has been observed. At present, it is apparent that both the deaminase-dependent and -independent pathways are tightly involved not only in combating viruses but also in human tumorigenesis. Although the deaminase-dependent pathway has been extensively characterized so far, understanding of the deaminase-independent pathway remains immature. Here, we review existing knowledge regarding the deaminase-independent antiretroviral functions of APOBEC3s and their molecular mechanisms. We also discuss the possible unidentified molecular mechanism for the deaminase-independent antiretroviral function mediated by mouse APOBEC3.

scholarly journals ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity

2018 ◽  
Vol 131 (24) ◽  
pp. jcs222273 ◽  
Author(s):  
Sonam Gurung ◽  
Ashley J. Evans ◽  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Synaptic Activity ◽  
Kainate Receptor

scholarly journals ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins

2018 ◽  
Vol 115 (41) ◽  
pp. E9717-E9726 ◽  
Author(s):  
Hourinaz Behesti ◽  
Taylor R. Fore ◽  
Peter Wu ◽  
Zachi Horn ◽  
Mary Leppert ◽  
...  
Keyword(s):  
Surface Protein ◽  
Surface Expression ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Surface Proteins ◽  
Synaptic Activity ◽  
Synaptic Proteins ◽  
Immunogold Electron Microscopy ◽  
Dynamic Regulation ◽  
Cerebellar Purkinje Cells

Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immunogold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII domain, recurrently disrupted by CNVs in patients, including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.

NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

2001 ◽  
Vol 280 (6) ◽  
pp. R1815-R1822 ◽  
Author(s):  
Javier E. Stern ◽  
Mike Ludwig
Keyword(s):  
Neuronal Excitability ◽  
Cell Types ◽  
Synaptic Activity ◽  
No Donor ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Neuronal Types ◽  
Vasopressin Neurons

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

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