Extracellular Phosphorylation of a Receptor Tyrosine Kinase Controls Synaptic Localization of NMDA Receptors and Regulates Pathological Pain


Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB-NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function.

Includes supplementary material
Alzheimer's disease, Bones—Cancer, Receptors, N-Methyl-D-Aspartate, Posterior Horn Cells, Receptors, Eph Family, Neuralgia, Receptors, Purinergic P2X, Vesicular Glutamate Transport Proteins
National Institute of Mental Health (grant number MH100093). National Institute of General Medicine (grant number GM102575). National Center for Research Resources (grant number RR027990). National Institute on Drug Abuse (grant number DA022727). National Eye Institute Vision Training Grant (grant number EY007035). National Institute of Neurological Disorders and Stroke (grant number NS050276). National Institute of Neurological Disorders and Stroke (grant number NS065926).
CC BY 4.0 (Attribution), ©2017 The Authors