REGULATION OF NMDA RECEPTORS BY TYROSINE KINASES AND PHOSPHATASES

PROTEIN-TYROSINE kinases (PTKs) and protein-tyrosine phosphatases (PTP s) are key enzymes in signal-transduction pathways for a wide range of cellular processes(1,2). PTKs and PTPs are highly expressed in the ce ntral nervous system(3), which is consistent with the importance of ty rosine phosphorylation in neuronal function(4-6). Protein phosphorylat ion is known to be involved in the regulation of neurotransmitter rece ptors(7,8), but the effects of tyrosine phosphorylation on neurotransm itter receptor function in the central nervous system are unknown. Her e we present evidence that in mammalian central neurons tyrosine phosp horylation regulates the function of the NMDA (N-methyl-D-aspartate) r eceptor, a subtype of excitatory amino-acid receptor(9,10). NMDA-recep tor-mediated whole-cell currents and intracellular Ca2+ responses are depressed by inhibition of PTKs. Conversely, NMDA currents are potenti ated by intracellular application of the well characterized PTK pp60(c -src). NMDA currents are also potentiated by intracellular administrat ion of an inhibitor of PTPs. Protein-tyrosine phosphorylation is a new mechanism for regulating NMDA receptors and may be important in neuro nal development, plasticity and toxicity.