High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling

Herman B. Fernandes; Justin S. Catches; Ronald S. Petralia; Bryan A. Copits; Jian Xu; Theron A. Russell; Geoffrey T. Swanson; Anis Contractor

doi:10.1016/j.neuron.2009.08.010

High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling

Herman B. Fernandes, Justin S. Catches, Ronald S. Petralia, Bryan A. Copits, Jian Xu, Theron A. Russell, Geoffrey T. Swanson, Anis Contractor^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

99 Scopus citations

Abstract

Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (I_sAHP), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.

Original language	English (US)
Pages (from-to)	818-829
Number of pages	12
Journal	Neuron
Volume	63
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2009.08.010
State	Published - Sep 24 2009

Funding

We gratefully thank Professor Stephen Heinemann in whose laboratory the floxed GluK4 mice were originally generated. Ashley Westwood provided technical help with mouse husbandry and genotyping and Dr Ya-Xian Wang contributed to the immunogold labeling. This work was supported by extramural grants from the National Institute of Health (NINDS) (R01NS044322 to G.T.S. and R01NS058894 to A.C.) and NIH intramural support (NIDCD) (to R.S.P.). Justin Catches is a John N. Nicholson Fellow.

Keywords

MOLNEURO
SIGNALING

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2009.08.010

Cite this

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title = "High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling",

abstract = "Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (IsAHP), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.",

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note = "Funding Information: We gratefully thank Professor Stephen Heinemann in whose laboratory the floxed GluK4 mice were originally generated. Ashley Westwood provided technical help with mouse husbandry and genotyping and Dr Ya-Xian Wang contributed to the immunogold labeling. This work was supported by extramural grants from the National Institute of Health (NINDS) (R01NS044322 to G.T.S. and R01NS058894 to A.C.) and NIH intramural support (NIDCD) (to R.S.P.). Justin Catches is a John N. Nicholson Fellow. ",

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AU - Xu, Jian

AU - Russell, Theron A.

AU - Swanson, Geoffrey T.

AU - Contractor, Anis

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N2 - Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (IsAHP), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.

AB - Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (IsAHP), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.

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High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling

Abstract

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Keywords

ASJC Scopus subject areas

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