Abstract
NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.
Highlights
NMDA receptors (NMDARs) are ligand-gated Ca2+-permeable channels that consist of GluN1, GluN2 (GluN2A-GluN2D), and GluN3 (GluN3A-GluN3B) subunits (Monyer et al, 1992)
To determine whether AMPA receptors (AMPARs) function is regulated by a metabotropic activity of NMDARs, we measured the effect of NMDAR co-agonist glycine on AMPAR function in cultured mouse hippocampal neurons in which the channel activity of NMDARs was inhibited by a Ca2+-free extracellular solution (ECS) in which Ca2+ was not included but with the addition of MK-801 (10 μM), EGTA (5.0 mM) and strychnine (10 μM)
This Ca2+-free ECS with the inclusion of MK-801 (MacDonald and Nowak, 1990; Rosenmund et al, 1993) and the Ca2+ chelator EGTA ensured that no Ca2+ passed through NMDAR channels, The glycine receptor antagonist strychnine was included in the Ca2+-free ECS to exclude the possible effects mediated by glycine activation of glycine receptors (Lynch, 2004)
Summary
NMDA receptors (NMDARs) are ligand-gated Ca2+-permeable channels that consist of GluN1, GluN2 (GluN2A-GluN2D), and GluN3 (GluN3A-GluN3B) subunits (Monyer et al, 1992). NMDARs mediate excitatory neurotransmission (Dingledine et al, 1999), which play essential roles in synaptic plasticity (Malenka and Nicoll, 1999; Barria and Malinow, 2002), neural development (Constantine-Paton et al, 1990; Kerchner and Nicoll, 2008) and glutamate-induced neurotoxicity (Choi, 1988; Aarts et al, 2002; Tu et al, 2010). The agonist glutamate binding to GluN2 subunits and co-agonist glycine binding to GluN1 subunits are required to activate the Metabotropic Activation of GluN2A-Containing NMDA Receptor channel activity of NMDARs (Johnson and Ascher, 1987). J. et al, 2005), which is considered to be a postsynaptic mechanism for the regulation of synaptic plasticity including calciumdependent long-term potentiation (Malinow and Malenka, 2002; Collingridge et al, 2004; Li et al, 2010; Man, 2011; Lu and Roche, 2012)
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