Faculty Opinions recommendation of Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain.
The direct interaction between N-methyl-D-aspartate receptors (NMDARs) and the extracellular domain of the EphB receptor tyrosine kinases (RTKs) is essential for proper neuronal communication and NMDAR signaling. The molecular mechanisms mediating these interactions are unclear. This is the first study showing that extracellular tyrosine phosphorylation occurs in the nervous system. Mechanistically, ephrin-B ligand-dependent extracellular phosphorylation of EphB2 receptor tyrosine kinase at a single residue is necessary and sufficient to promote NMDAR-EphB interaction at synaptic sites in cortical and spinal cord neurons. Most importantly, the authors identified a functional significance of this extracellular phosphorylation. Intrathecal injection of activated ephrin-B enhanced NMDAR-EphB interaction and modulated animal behavior, whereas blocking extracellular kinase activity with the membrane-impermeant drug K252b significantly reduced mechanical hypersensitivity in adult mice. Secreted kinases are capable of phosphorylating extracellular protein substrates. The data from this study constitute the beginning of understanding the biological consequences of extracellular phosphorylation.