It pays to consider both sides of protein phosphorylation—not just the well-studied intracellular side, but also the relatively neglected extracellular side. Whether they float inside the cell, cling to its internal surfaces, or even stud its exterior, proteins that are subject to structure- and function-altering phosphorylation reactions may participate in signaling cascades that are initiated by extracellular stimuli. It’s just that in some instances, external stimuli may cause phosphorylation sooner rather than later.

In a new study, a receptor protein has been found to undergo extracellular phosphorylation and thereby trigger signaling that has consequences for pathogenic pain, the sort of pain that has no underlying cause or persists long after the initiating event is past—the sort of pain that is associated with migraines. This discovery, from a study conducted by scientists based at Thomas Jefferson University, suggests that new drugs could be developed that would interfere with the receptor protein’s phosphorylation. Such drugs would bring relief to people who suffer pathogenic pain, which often comes from neuronal dysfunction, as opposed to inflammation or impact.

More generally, the discovery suggests that extracellular phosphorylation of proteins is an underappreciated mechanism that contributes to the development and function of synapses, neurons, and the nervous system.

Detailed findings appeared July 18 in the journal PLOS Biology, in an article entitled “Extracellular Phosphorylation of a Receptor Tyrosine Kinase Controls Synaptic Localization of NMDA Receptors and Regulates Pathological Pain.” The article reinforces the idea that proteins must be in the right place at the right time in the cell to function correctly, an idea that is especially pertinent to understanding neuronal function.

Unlike other cells, neurons have complex tree-like structures. Consequently, in neurons, changes in protein localization could affect the composition and function of synapses, potentially altering synaptic plasticity, which could have a role in pain sensation.

“Here we describe a single extracellular tyrosine whose inducible phosphorylation may represent an archetype for a new class of mechanism mediating protein—protein interaction and regulating protein function,” wrote the authors of the PLOS Biology article. “We show that the interaction between EphB2—which occurs upon receptor activation by its ligand ephrin-B—and the N-methyl-D-aspartate receptor (NMDAR) depends on extracellular phosphorylation of EphB2. This interaction regulates the localization of the NMDA receptor to synaptic sites in neurons.”

Previous research had shown that the NMDA receptor on neurons plays a central role in pathologic pain, but this receptor is also important in many other neurological processes, such as memory and learning, making it a poor target for direct drug inhibition.

In an elegant series of studies, Thomas Jefferson University’s Matthew Dalva, Ph.D., along with colleagues from New York University and the University of Texas at Dallas, showed that in response to pain, a second receptor, the ephrin B receptor, is phosphorylated outside of the neuron. This extracellular protein modification allows the ephrin B receptor EphB2 to glom onto the NMDA receptor. This interaction then moves the NMDA receptors into the synaptic space and modifies NMDA receptor function, resulting in increased pain sensitivity.

The researchers also showed that chemicals that block the interaction between the EphB2 and the NMDA receptor block pain. The converse was also true. By artificially promoting the interaction between these two receptors, neurons became oversensitive to pain, such that a mere touch would cause a painful reaction, or allodynia.

“Because the protein modification that initiates nerve sensitivity to pain occurs outside of the cell, it offers us an easier target for drug development,” said Dr. Dalva. “This is a promising advance in the field of pain management.”

The discovery that phosphorylation can drive NMDA receptors to synaptic sites provides neuroscientists a new tool with which to study synaptic development, learning and memory, and pain—all of which depend on the localization of NMDA receptors to synaptic sites.

“Although we have yet to discover the exact mechanism that causes this modification,” noted Dr. Dalva, “this finding offers both a target for developing new treatments and a strong new tool for studying synapses in general.”

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