Glycine binding primes NMDA receptor internalization

Abstract

NMDA (N-methyl-d-aspartate) receptors (NMDARs) are a principal subtype of excitatory ligand-gated ion channel with prominent roles in physiological and disease processes in the central nervous system. Recognition that glycine potentiates NMDAR-mediated currents as well as being a requisite co-agonist of the NMDAR subtype of 'glutamate' receptor profoundly changed our understanding of chemical synaptic communication in the central nervous system. The binding of both glycine and glutamate is necessary to cause opening of the NMDAR conductance pore. Although binding of either agonist alone is insufficient to cause current flow through the channel, we report here that stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. Glycine binding alone does not cause the receptor to be endocytosed; this requires both glycine and glutamate site activation of NMDARs. The priming effect of glycine is mimicked by the NMDAR glycine site agonist d-serine, and is blocked by competitive glycine site antagonists. Synaptic as well as extrasynaptic NMDARs are primed for internalization by glycine site stimulation. Our results demonstrate transmembrane signal transduction through activating the glycine site of NMDARs, and elucidate a model for modulating cell-cell communication in the central nervous system.

Theanine, γ-glutamylethylamide, a unique amino acid in tea leaves, modulates neurotransmitter concentrations in the brain striatum interstitium in conscious rats

“…This result suggested that the increases of glycine in the interstitium by theanine might have influenced dopamine release via glycine receptors. Although glycine is known as a major inhibitory neurotransmitter, glycine combines with the glycine binding site of the NMDA receptor and enhances excitatory neurotransmission (Xu et al 1999;Kuhse et al 1995;Nong et al 2003). Glycine enhanced NMDA evoked dopamine release, and 7-chloro-kynurenate, an NMDA antagonist, acting on a glycine site, markedly reduced this response (Martinez et al 1992); however, 5,7-DCKA injection did not prevent the increase of dopamine concentration by theanine injection in this study.…”

Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1

“…Although this seems to be the case in mature neurons, NMDARs move rapidly into and out of synapses in developing neurons 15,18,34 . It is likely that synaptic removal of NMDARs involves a combination of lateral diffusion 15,34 and endocytosis [16][17][18] . Although the mechanisms have been unclear, this process is almost certainly determined by a balance between interactions with scaffolding proteins that anchor receptors at the PSD, and interactions with adaptors that target NMDARs to the endocytic machinery for membrane removal 25 .…”

“…Substantial evidence also supports a role for exocytic and endocytic receptor cycling in controlling AMPAtype glutamate receptor abundance at synapses during synaptic plasticity, but NMDARs have conventionally been thought to be stably fixed within the postsynaptic density (PSD). Challenging this view, recent studies have revealed that NMDARs can move rapidly in and out of the neuronal surface [14][15][16][17][18][19][20] . Atleast some forms of NMDAR exocytic and endocytic trafficking require synaptic activity 21 or ligand binding 17,22 ,23 , and may initiate synaptic changes that lead to synapse stabilization or elimination during development 16,23 . Despite recent progress, our knowledge of how postsynaptic NMDARs are linked to and regulated by the endocytic machinery is only just emerging.…”

“…Ligand binding promotes NMDAR downregulation 18,22 and synaptic replacement 23 , and simultaneously stimulates the association of NMDARs with AP-2 (ref. 17), suggesting the regulated recruitment of the clathrin endocytic machinery.…”

Glycine Uptake Regulates Hippocampal Network Activity via Glycine Receptor-Mediated Tonic Inhibition

“…However, recent reports demonstrate that the dominant endogenous co-agonist for NMDAR neurotoxicity is D-serine but not glycine (Shleper et al, 2005). Furthermore, high concentrations of glycine prime NMDAR internalization (Nong et al, 2003), which may lead to a concentration-dependent dual regulation of NMDAR-mediated responses. Additional studies report that GlyRs can affect GABAergic responses through crossinhibition between GlyRs and GABA A receptors (GABA A Rs) (Li and Xu, 2002;Li et al, 2003).…”