A new study reports on the discovery of a phosphorylation event outside of the cell, which gives researchers a new avenue for targeting chronic and pathologic pain.
According to the researchers from Thomas Jefferson University, proteins must be in the right place and at the right time in the cell to function properly, and is even more critical in a neuron because of its complex tree-like structure, as well as, its overall function.
The researchers discovered how phosphorylation, which is a common type of protein modification, functions in a novel way to change the location of proteins that are critical for both the function of neurons and pathological pain. Phosphorylation, it seems, can occur outside of a neuron and it impacts protein function, localization and the sensation of pain.
The research, which was in PLOS Biology, offers a potential new target for developing an alternative to existing pain management approaches.
“Although we have yet to discover the exact mechanism that causes this modification, this finding offers both a target for developing new treatments and a strong new tool for studying synapses in general,” said senior author Matthew Dalva, Ph.D., Professor and Vice Chair in the Department of Neuroscience in The Vickie and Jack Farber Institute for Neuroscience at the Sidney Kimmel Medical College, Thomas Jefferson University,
Pathological pain often comes from neuronal dysfunction, where pain is felt even when there is no identifiable cause, which results in what we know as chronic pain.
Researchers have shown that the NMDA receptor on neurons plays a central role in pathologic pain, but it’s also important in many other neurological processes such as memory and learning, which makes it difficult to target with drugs.
Dr. Dalva and colleagues 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 grab onto the NMDA receptor. This 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,” says 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.