Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

Rojas, Asheebo; Wetherington, Jonathon P.; Shaw, Reneé; Serrano, Geidy E.; Swanger, Sharon A.; Dingledine, Raymond

doi:10.1124/mol.112.081802

Cited by 9 publications

(28 citation statements)

References 56 publications

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“…We treated control and tau knockdown neurons with Aβ 42 prior to KA treatment and found that Aβ 42 had a biphasic effect on the KA-induced Ca 2+ cyt response and that this effect was not prevented by the reduction of tau expression. The biphasic effect of Aβ 42 we observed on KA-induced Ca 2+ influx mimics previously demonstrated modulation of KAR by group 1 mGluRs and protein kinase C (PKC) (Cho et al, 2003; Nasu-Nishimura et al, 2010; Rojas et al, 2013). In addition, Aβ has previously been shown to activate group 1 mGluRs and elicit downstream effects on glutamate receptor activity (Um et al, 2012; Um et al, 2013).…”

Section: Introductionsupporting

confidence: 87%

Mechanisms of tau and Aβ-induced excitotoxicity

et al. 2016

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Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer’s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau−/−) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca2+ influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca2+ influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca2+ influx. While Aβ biphasically modulated the KA-induced Ca2+cyt responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca2+ influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 minutes) enhanced KA-induced Ca2+ influx, while chronic Aβ (24 hours) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca2+ influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1 mGluR activation.

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Section: Introductionsupporting

confidence: 87%

Mechanisms of tau and Aβ-induced excitotoxicity

et al. 2016

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“…There was an interesting difference between the findings by Rojas et al (2013) and Cho et al (2003), namely the involvement of Ca 21 mobilization in the regulation of KARs by group I mGlu receptors. In the Cho et al (2003) study the mGlu5-mediated potentiation of (R,S)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid-activated KAR currents was calcium-independent; however, in Rojas et al (2013), the potentiation of heteromeric KARs by activation of group I mGlu receptors was clearly calcium-dependent, as the potentiation was lost in the presence of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N9,N9-tetraacetic acid. This difference in the contribution of a critical signaling molecule suggests that there may be multiple pathways regulating KARs following mGlu receptor activation.…”

Section: Kainate Receptorscontrasting

confidence: 44%

“…It was also not clear which subunits of KAR were involved in the modulation. Rojas et al (2013) recently demonstrated the regulation of heteromeric KARs by group I mGlu receptors in cultured cortical and hippocampal neurons and Xenopus oocytes. Pronounced potentiation of heteromeric KAR (consisting of high-and low-affinity subunits) currents was observed following activation of group I mGlu receptors (Fig.…”

Section: Kainate Receptorsmentioning

confidence: 99%

“…Site-directed mutagenesis led to the identification of three serines in the GluK5 subunit that are responsible for PKC-mediated potentiation of KAR by group I mGlu receptors (Fig. 2, C and D; Rojas et al, 2013). Selak et al (2009) reported reduced GluK5 expression via PKC-mediated disruption of the interaction of GluK5 with the synaptic proteins SNAP-25 and PICK1.…”

Section: Kainate Receptorsmentioning

confidence: 99%

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

Rojas

Dingledine

2013

Mol Pharmacol

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The function of many ion channels is under dynamic control by coincident activation of G-protein-coupled receptors (GPCRs), particularly those coupled to the G as and G aq family members. Such regulation is typically dependent on the subunit composition of the ionotropic receptor or channel as well as the GPCR subtype and the cell-specific panoply of signaling pathways available. Because GPCRs and ion channels are so highly represented among targets of U.S. Food and Drug Administration-approved drugs, functional cross-talk between these drug target classes is likely to underlie many therapeutic and adverse effects of marketed drugs. GPCRs engage a myriad of signaling pathways that involve protein kinases A and C (PKC) and, through PKC and interaction with b-arrestin, Src kinase, and hence the mitogen-activated-protein-kinase cascades. We focus here on the control of ionotropic glutamate receptor function by GPCR signaling because this form of regulation can influence the strength of synaptic plasticity. The amino acid residues phosphorylated by specific kinases have been securely identified in many ionotropic glutamate (iGlu) receptor subunits, but which of these sites are GPCR targets is less well known even when the kinase has been identified. N-methyl-D-aspartate, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and heteromeric kainate receptors are all downstream targets of GPCR signaling pathways. The details of GPCR-iGlu receptor cross-talk should inform a better understanding of how synaptic transmission is regulated and lead to new therapeutic strategies for neuropsychiatric disorders.

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“…Like GABA B receptors, the end result of triggering this reaction cascade may be modulation of ionotropic receptors. For example, group I metabotropic glutamate receptors have been shown to be able to potentiate the responses of kainate receptors in the hippocampus and cerebral cortex in rats [37]. The postsynaptic glutamate receptors of cortical pyramidal cells have also been shown to modulate the operation of ionotropic NMDA-type glutamate receptors [6,44].…”

Section: Modulation Of Gaba-andmentioning

confidence: 98%

Modulation of GABA- and Kainate-Mediated Ion Currents in Isolated Rat Cerebral Cortex Neurons by Metabotropic Receptors

Amakhin

Popov

Veselkin

2016

Neurosci Behav Physi

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GABA and glutamate are two of the main neurotransmitters in the mammalian brain. Both substances can activate both ionotropic receptors (GABA A receptors and NMDA, AMPA, and kainate glutamate receptors) and metabotropic receptors (GABA B and a multiplicity of subtypes of metabotropic glutamate receptors), located both pre-and postsynaptically. This creates conditions in which mutual modulation of these receptors could occur [1,39].Postsynaptic GABA B receptors are present in the rat cerebral cortex [34], are coupled with G-proteins of the Gi/o type, and their activation can lead to various intracellular reactions, the main of which are a decrease in adenylate cyclase activity and a resultant reduction in protein kinase A activity [7,15,30]. Activation of this intracellular cascade leads to various changes in the activity of intracellular signal molecules [15,19]. The effects of activation of GABA B receptors may include modulation of ionotropic receptors, as many of these have sites for intracellular signal molecules. Thus, the intracellular domains of various GABA A receptor subunits have sites specifi c for protein kinases A, C, and G, calcium/calmodulin-dependent kinase Cam KII, and tyrosine kinases [9, 17, 18, 22-28, 35, 45, 46].There are presently several lines of evidence for modulation of the various ionotropic receptors via GABA B receptors. Baclofen, a GABA B receptor agonist, has been demonstrated to produce an irreversible decrease in the amplitude of the current induced by application of glycine in frog spinal cord neurons [3].Patch clamp experiments with fi xation of the membrane potential were performed on isolated rat prefrontal cortex neurons to study the modulation of ion currents induced by applications of GABA and kainate by GABA B receptors and group I metabotropic glutamate receptors. Blockade of GABA B receptors with the selective antagonist CGP-55845 (5 μM) increased the peak amplitude of the ion current induced by application of GABA (40 μM) by 26 ± 13% (n = 6). The amplitude of the ion current plateau at 14 sec of application of GABA was the same in controls as with blockade of GABA B receptors. The long-term effects of activation of GABA B receptors were studied in terms of the responses to application of GABA and kainate in the presence of baclofen (50 μM), a selective GABA B receptor agonist. Prolonged prior application of baclofen increased the amplitude of responses to application of GABA by 9 ± 2% (n = 8) as compared with controls. Responses to application of kainate did not change in the presence of baclofen. Analogous experiments using trans-ACPD, a selective agonist of groups I and II metabotropic glutamate receptors, did not reveal any changes in responses to application of GABA or kainate. These data point to modulation of GABA A receptors by postsynaptic metabotropic GABA B receptors in rat cerebral cortex neurons.

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Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

Cited by 9 publications

References 56 publications

Mechanisms of tau and Aβ-induced excitotoxicity

Mechanisms of tau and Aβ-induced excitotoxicity

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

Modulation of GABA- and Kainate-Mediated Ion Currents in Isolated Rat Cerebral Cortex Neurons by Metabotropic Receptors

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