Glycine binding primes NMDA receptor internalization

Yi Nong, Yue-Qiao Huang, William Ju, Lorraine V. Kalia, Gholamreza Ahmadian, Yu Tian Wang () and Michael W. Salter ()
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Yi Nong: University of Toronto
Yue-Qiao Huang: University of Toronto
William Ju: University of Toronto
Lorraine V. Kalia: University of Toronto
Gholamreza Ahmadian: University of Toronto
Yu Tian Wang: University of Toronto
Michael W. Salter: University of Toronto

Nature, 2003, vol. 422, issue 6929, 302-307

Abstract: 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 system1. Recognition that glycine potentiates NMDAR-mediated currents2 as well as being a requisite co-agonist of the NMDAR subtype of ‘glutamate’ receptor3 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 pore1. 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.

Date: 2003
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DOI: 10.1038/nature01497

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