Kainate receptors coming of age: milestones of two decades of research

Contractor, Anis; Mulle, Christophe; Swanson, Geoffrey T.

doi:10.1016/j.tins.2010.12.002

Cited by 256 publications

(304 citation statements)

References 150 publications

(181 reference statements)

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“…KAR EPSCs are also roughly 10% of their grander glutamatergic cousins, and they are also markedly slower, with time constants on the order of 50-100 ms (62,64). This prolonged decay appears to be important for summation, temporal integration, and, ultimately, induction of potentiation (65)(66)(67). Taken together, the studies of KAR EPSCs indicate that the small amplitude of ASIC EPSCs, by itself, is not sufficient to preclude a physiological role.…”

Section: Discussionmentioning

confidence: 96%

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

MacLean

Jayaraman

2017

Proc. Natl. Acad. Sci. U.S.A.

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Acid-sensing ion channels (ASICs) are trimeric cation-selective ion channels activated by protons in the physiological range. Recent reports have revealed that postsynaptically localized ASICs contribute to the excitatory postsynaptic current by responding to the transient acidification of the synaptic cleft that accompanies neurotransmission. In response to such brief acidic transients, both recombinant and native ASICs show extremely rapid deactivation in outside-out patches when jumping from a pH 5 stimulus to a single resting pH of 8. Given that the resting pH of the synaptic cleft is highly dynamic and depends on recent synaptic activity, we explored the kinetics of ASIC1a and 1a/2a heteromers to such brief pH transients over a wider [H + ] range to approximate neuronal conditions better. Surprisingly, the deactivation of ASICs was steeply dependent on the pH, spanning nearly three orders of magnitude from extremely fast (<1 ms) at pH 8 to very slow (>300 ms) at pH 7. This study provides an example of a ligand-gated ion channel whose deactivation is sensitive to agonist concentrations that do not directly activate the receptor. Kinetic simulations and further mutagenesis provide evidence that ASICs show such steeply agonist-dependent deactivation because of strong cooperativity in proton binding. This capacity to signal across such a large synaptically relevant bandwidth enhances the response to smallamplitude acidifications likely to occur at the cleft and may provide ASICs with the ability to shape activity in response to the recent history of the synapse.acid-sensing ion channel | gating | kinetics | ligand-gated ion channel N eurotransmitter levels within the synaptic cleft rise and fall very rapidly, with clearance times generally on the order of a few hundred microseconds to 2 ms (1-3). However, the duration of responses from neurotransmitter-gated ion channels (NGICs) varies widely across several orders of magnitude depending on the receptors involved. For example, in certain regions, glutamatergic excitatory postsynaptic currents (EPSCs) decay with submillisecond time constants (4), but the EPSCs of GluN2D-containing NMDA receptors decay over roughly 200 ms (5, 6). Such differences in the decay or deactivation of NGIC responses can profoundly impact the window of synaptic excitability and integration (4,7,8). Control over NGIC kinetics is also a powerful force during development, where slower receptor subtypes tend to be used early on, broadening the window of plasticity during critical periods, and later give way to faster decaying subunits providing greater temporal precision (9-13). This trade-off between the window of integration on the one hand and temporal precision on the other persists in the mature brain. There, synapses host an NGIC compliment kinetically suited to their input patterns (14) but are also capable of dynamically shifting between the priorities of integration and precision (8). Unsurprisingly then, influencing the deactivation kinetics of specific NGIC subtypes using allosteri...

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Section: Discussionmentioning

confidence: 96%

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

MacLean

Jayaraman

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…KAR subtypes subserve a variety of functions that depend in part on their subcellular localization (Contractor et al, 2011). It has not yet been possible to link specific KAR subunits with a particular subcellular localization in neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Some iGluRs are also present at presynaptic terminals, where they regulate neurotransmitter release (Pinheiro and Mulle, 2008). Kainate receptors (KARs), composed of various combinations of the five subunits GluK1-5 (formerly referred as GluR5-7, KA1, and KA2), display a variety of functions that concur with the regulation of the activity of synaptic networks by actions at presynaptic and postsynaptic sites (Contractor et al, 2011). The electrophysiological analysis of KAR-subunit deficient mice has indicated that GluK2 and GluK3 are essential components of presynaptic autoreceptors (Contractor et al, 2001;Pinheiro et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Endocytosis of the Glutamate Receptor Subunit GluK3 Controls Polarized Trafficking

Huyghe

Veran²,

Labrousse³

et al. 2011

J. Neurosci.

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Kainate receptors (KARs) are widely expressed in the brain and are present at both presynaptic and postsynaptic sites. GluK3-containing KARs are thought to compose presynaptic autoreceptors that facilitate hippocampal mossy fiber synaptic transmission. Here we identify molecular mechanisms that underlie the polarized trafficking of KARs composed of the GluK3b splice variant. Endocytosis followed by degradation is driven by a dileucine motif on the cytoplasmic C-terminal domain of GluK3b in heterologous cells, in cultured hippocampal neurons, and in dentate granule cells from organotypic slice cultures. The internalization of GluK3b is clathrin and dynamin2 dependent. GluK3b is differentially endocytosed in dendrites as compared to the axons. These data suggest that the polarized trafficking of KARs in neurons could be controlled by the regulation of receptor endocytosis.

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“…Kainic acid (KA), an epileptogenic and neuro-excitotoxic agent, is widely used for inducing neurodegeneration in animal studies (4)(5)(6). It is a specific agonist for kainate receptors, which are ionotropic glutamatergic receptors that modulate transmission and excitability.…”

Section: +mentioning

confidence: 99%

The use of manganese-enhanced MRI for the evaluation of neurodegenerative changes in a rat model of kainic acid- induced excitotoxicity

Apaydin

Evren²,

Erbaş³

et al. 2013

Diagn Interv Radiol

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NEURORADIOLOGYORIGINAL ARTICLE PURPOSE Manganese-enhanced magnetic resonance imaging (MEM-RI) has been used to detect brain activity based on the ability of active neurons to take up manganese ions through calcium channels. Kainic acid (KA), an analog of excitotoxic glutamate, can elicit selective neuronal death in the brains of rodents, of which the pathological changes partially mimic neurodegeneration in the central nervous system. We used in vivo MEMRI to evaluate neurodegenerative changes in an excitotoxicity model induced by KA in rats. MATERIALS AND METHODSAdult Sprague-Dawley rats (220-250 g) were injected with either KA or saline into the right lateral ventricle. Precontrast and postcontrast MEMRI sessions were obtained. Region of interest (ROI) analyses were performed on both injected (saline and KA) and contralateral (normal) sites in the hippocampal area. All brains were evaluated histologically following MEMRI. RESULTSAnalysis of percentage change in ROI intensities of T1-weighted fluid-attenuated inversion-recovery MR images in the hippocampal area revealed a significant difference between the KA-injected (ipsilateral) and contralateral sites (P = 0.008), whereas no significant difference was observed between the saline-injected and contralateral sites. Furthermore, there was a significant difference between ipsilateral sites of the saline-treated and KA-treated groups (P = 0.026). The histological results supported these findings. CONCLUSION MEMRI is a simple and useful in vivo method for detecting neurodegenerative changes due to excitotoxicity in the rat brain. The development of a manganese-based contrast agent that can be safely used in humans is warranted to investigate neurological disorders.

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Kainate receptors coming of age: milestones of two decades of research

Cited by 256 publications

References 150 publications

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

Endocytosis of the Glutamate Receptor Subunit GluK3 Controls Polarized Trafficking

The use of manganese-enhanced MRI for the evaluation of neurodegenerative changes in a rat model of kainic acid- induced excitotoxicity

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