Distinct Subunits in Heteromeric Kainate Receptors Mediate Ionotropic and Metabotropic Function at Hippocampal Mossy Fiber Synapses

Ruiz, A. (2005) Distinct Subunits in Heteromeric Kainate Receptors Mediate Ionotropic and Metabotropic Function at Hippocampal Mossy Fiber Synapses. Journal of Neuroscience, 25 (50). pp. 11710-11718. 10.1523/JNEUROSCI.4041-05.2005.

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DOI: 10.1523/JNEUROSCI.4041-05.2005

Abstract

Heteromeric kainate receptors (KARs) containing both glutamate receptor 6 (GluR6) and KA2 subunits are involved in KAR-mediated EPSCs at mossy fiber synapses in CA3 pyramidal cells. We report that endogenous glutamate, by activating KARs, reversibly inhibits the slow Ca2+-activated K+ current IsAHP and increases neuronal excitability through a G-protein-coupled mechanism. Using KAR knockout mice, we show that KA2 is essential for the inhibition of IsAHP in CA3 pyramidal cells by low nanomolar concentrations of kainate, in addition to GluR6. In GluR6–/– mice, both ionotropic synaptic transmission and inhibition of IsAHP by endogenous glutamate released from mossy fibers was lost. In contrast, inhibition of IsAHP was absent in KA2–/– mice despite the preservation of KAR-mediated EPSCs. These data indicate that the metabotropic action of KARs did not rely on the activation of a KAR-mediated inward current. Biochemical analysis of knock-out mice revealed that KA2 was required for the interaction of KARs with Gαq/11-proteins known to be involved in IsAHP modulation. Finally, the ionotropic and metabotropic actions of KARs at mossy fiber synapses were differentially sensitive to the competitive glutamate receptor ligands kainate (5 nM) and kynurenate (1 mM). We propose a model in which KARs could operate in two modes at mossy fiber synapses: through a direct ionotropic action of GluR6, and through an indirect G-protein-coupled mechanism requiring the binding of glutamate to KA2.

Item Type:Article
Uncontrolled Keywords:hippocampus; CA3; kainate receptors; slow AHP; mossy fiber synapse; excitability; glutamate
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:2449
Journal or Publication Title:Journal of Neuroscience
Deposited By:Library Staff
Deposited On:11 Nov 2011 09:52
Last Modified:11 Nov 2011 09:52

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