A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux

Tyrosine phosphorylation can upregulate NMDA receptor activity during patho logical and physiological alterations of synaptic strength. Here we describ e downregulation of recombinant NR1/2A receptors by tyrosine dephosphorylat ion that requires agonist binding, but is independent of ion flux. The tyro sine residues involved in this new form of NMDA receptor modulation likely form a 'ring' adjacent to the last transmembrane domain. The downregulation was due to a reduction in the number of functional channels, and was block ed by co-expressing a dominant-negative mu2-subunit of the clathrin-adaptor protein AP-2. Our results provide a mechanism by which synaptic NMDA recep tors can be modulated in a use-dependent manner even when the postsynaptic membrane is not sufficiently depolarized to relieve channel block by magnes ium ions.