Letters to Nature

Nature 422, 302-307 (20 March 2003) | doi:10.1038/nature01497; Received 24 December 2002; Accepted 3 February 2003

Glycine binding primes NMDA receptor internalization

Yi Nong1,2,3, Yue-Qiao Huang1,2,3, William Ju1,3,4, Lorraine V. Kalia1,5, Gholamreza Ahmadian1,4, Yu Tian Wang1,4,6 & Michael W. Salter1,2,5

  1. Programme in Brain and Behaviour, Hospital for Sick Children, and Department of Physiology, Department of Pathobiology and Laboratory Medicine, and Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 1X8, Canada
  2. Department of Medicine and Brain Research Centre, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
  3. These authors contributed equally to this work

Correspondence to: Yu Tian Wang1,4,6Michael W. Salter1,2,5 Correspondence and requests for materials should be addressed to M.W.S. (e-mail: Email: mike.salter@utoronto.ca) or Y.T.W. (e-mail: Email: ytwang@interchange.ubc.ca).

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.