Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors

Rojas, Asheebo; Dingledine, Raymond

doi:10.1124/mol.112.083352

Cited by 43 publications

(50 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMPARs are composed of four types of subunits: GluR1-4. Through autocrine glutamate signaling, they contribute to enhanced glioma cell invasion (112,113). The subunits, especially GluR2, influence the cation permeability of AMPAR.…”

Section: Ion Channels and Their Contribution To Glioma Cell Migrationmentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

View full text Add to dashboard Cite

Gliomas are the most common intracranial tumors in humans. The most malignant among these tumors is glioblastoma (GBM), with an incidence of 3-5 out of 100,000 persons in Western countries. GBM arises either de novo (primary GBM) or develops from a lower grade glioma (secondary GBM). The prognosis is poor. GBMs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12-15 months. One characteristic that is responsible for GBM malignancy, and its worse prognosis, is the highly infiltrative growth of GBM cells into the healthy brain. GBM cell migration and invasion is a very complex process that is regulated by several factors, which include changes in the migrating cell itself as well as the tumor microenvironment. This chapter provides an overview of routes of invasion of glioma cells, the signaling pathways that drive glioma cell motility, and the processes through which glioma cells modulate their surrounding environment.

show abstract

Section: Ion Channels and Their Contribution To Glioma Cell Migrationmentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

View full text Add to dashboard Cite

show abstract

“…It was previously demonstrated that PKC-mediated phosphorylation of GluK2 C-terminal residues Ser-846 and Ser-868 regulates the recycling of GluK2 to the plasma membrane (19,(22)(23)(24). This led us to predict that if we promoted PKC-mediated GluK2 phosphorylation, we would also regulate KCC2 recycling.…”

Section: Pkc-mediated Phosphorylation Of Gluk2 Is Required For Gluk2 mentioning

confidence: 99%

A kainate receptor subunit promotes the recycling of the neuron-specific K+-Cl− co-transporter KCC2 in hippocampal neurons

Pressey

Mahadevan

Khademullah

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Roger J. ColbranSynaptic inhibition depends on a transmembrane gradient of chloride, which is set by the neuron-specific K ؉ -Cl ؊ co-transporter KCC2. Reduced KCC2 levels in the neuronal membrane contribute to the generation of epilepsy, neuropathic pain, and autism spectrum disorders; thus, it is important to characterize the mechanisms regulating KCC2 expression. In the present study, we determined the role of KCC2-protein interactions in regulating total and surface membrane KCC2 expression. Using quantitative immunofluorescence in cultured mouse hippocampal neurons, we discovered that the kainate receptor subunit GluK2 and the auxiliary subunit Neto2 significantly increase the total KCC2 abundance in neurons but that GluK2 exclusively increases the abundance of KCC2 in the surface membrane. Using a live cell imaging assay, we further determined that KCC2 recycling primarily occurs within 1-2 h and that GluK2 produces an ϳ40% increase in the amount of KCC2 recycled to the membrane during this time period. This GluK2-mediated increase in surface recycling translated to a significant increase in KCC2 expression in the surface membrane. Moreover, we found that KCC2 recycling is enhanced by protein kinase C-mediated phosphorylation of the GluK2 C-terminal residues Ser-846 and Ser-868. Lastly, using gramicidin-perforated patch clamp recordings, we found that the GluK2-mediated increase in KCC2 recycling to the surface membrane translates to a hyperpolarization of the reversal potential for GABA (E GABA ). In conclusion, our results have revealed a mechanism by which kainate receptors regulate KCC2 expression in the hippocampus.The classic fast hyperpolarizing inhibition of the mature brain results primarily from the activation of GABA A receptors.These receptors are Cl Ϫ -permeable ion channels, and inhibition results from the influx of Cl Ϫ into the neuron (1). This inward gradient for Cl Ϫ is set by the neuron-specific K ϩ /Cl Ϫ co-transporter KCC2 (2, 3). Despite the requirement of KCC2 for hyperpolarizing inhibition, the mechanisms that regulate KCC2 expression and function are still under intense investigation. In addition to the critical role KCC2 plays in synaptic inhibition, KCC2 is highly localized to excitatory synapses (4, 5), where it plays important roles in the development (6) and the function of glutamatergic synapses (7,8). In fact, single-particle tracking revealed that KCC2 is tightly confined to excitatory synapses (5), which may result from local protein interactions. Thus, understanding how proteins associated with excitatory synapses regulate KCC2 function may provide critical insight to the function of KCC2.KCC2 exists in a multiprotein complex and is regulated by components of excitatory synaptic transmission (9 -11). Specifically, KCC2 interacts with both the kainate-type ionotropic glutamate receptor subunit GluK2 (9) and its auxiliary subunit Neto2 (10). Neto2 regulates KCC2-mediated Cl Ϫ extrusion by binding to the active oligomeric form of KCC2 (10), whereas the GluK2-KCC2 i...

show abstract

“…Glutamate binds to post-synaptic glutamate receptors, including ionotropic glutamate, kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA) receptors [18]. Glutamate-induced excitotoxicity is considered an important mechanism underlying neuronal death in ischemia, CNS trauma, and epilepsy [19].…”

Section: Glutamatementioning

confidence: 99%