Distinct subunits in heteromeric kainate receptors mediate ionotropic and metabotropic function at hippocampal mossy fiber synapses
Journal of Neuroscience. 2005-12-14; 25(50): 11710-11718
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1. J Neurosci. 2005 Dec 14;25(50):11710-8.
Distinct subunits in heteromeric kainate receptors mediate ionotropic and
metabotropic function at hippocampal mossy fiber synapses.
Ruiz A(1), Sachidhanandam S, Utvik JK, Coussen F, Mulle C.
(1)Laboratoire de Physiologie Cellulaire de la Synapse, Centre National de la
Recherche Scientifique, Unité Mixte de Recherche 5091, Université Bordeaux 2,
33077 Bordeaux, France.
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 I(sAHP) and increases
neuronal excitability through a G-protein-coupled mechanism. Using KAR knockout
mice, we show that KA2 is essential for the inhibition of I(sAHP) in CA3
pyramidal cells by low nanomolar concentrations of kainate, in addition to GluR6.
In GluR6(-/-) mice, both ionotropic synaptic transmission and inhibition of
I(sAHP) by endogenous glutamate released from mossy fibers was lost. In contrast,
inhibition of I(sAHP) 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
Galpha(q/11)-proteins known to be involved in I(sAHP) 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.
PMID: 16354929 [Indexed for MEDLINE]