In a major brain science breakthrough, New Orleans-based researchers and collaborators have discovered a nerve signaling mechanism that takes place outside the cell, flipping on a 'pain switch.' This significantly updates the way we understand how pain receptors work in the brain, and it could shed light on a path to safer pain medication that can effectively provide relief without the usual side effects.
The scientists acknowledged that phosphorylation – a key process by which proteins are regulated – was generally understood when it occurred inside a cell, but its function outside the cell was less clear. They wanted to know if this modification, which occurs on the exterior parts of many synaptic proteins, actually changes how nerve connections (synapses) signal or affects behavior in a living animal.
They found that nerve cells communicate outside the cell with an enzyme called vertebrate lonesome kinase (VLK); this enzyme alters proteins in the space between neurons. When active neurons release VLK, it boosts the function of a pain receptor. This finding "opens up an entirely new way of thinking about how to influence cell behavior and potentially a simpler way to design drugs that act from the outside rather than having to penetrate the cell," noted Matthew Dalva, a brain scientist at Tulane University who led the study on this mechanism that appeared in the journal Science last week.
When the team removed VLK from pain-sensing neurons in mice, the animals didn’t feel the usual pain that followed surgery, and continued to experience sensations from their surroundings as normal; amping up the level of VLK in those neurons increased the pain responses.
In other words, "an enzyme released by neurons can modify proteins on the outside of other cells to turn on pain signaling – without affecting normal movement or sensation," Dalva explained.
This is important because it gives us a new way to think about developing drugs to treat pain by affecting cells from the outside rather than having to penetrate the cell. By targeting enzymes like VLK instead of blocking receptors at synapses (which can result in side effects), we might have an easier go at delivering pain relief.
Naturally, a lot more work will be involved in exploring the implications of this finding before we see next-gen pain drugs based on it. The researchers plan to follow up this work by determining how broadly this affects proteins involved in neurological functioning, and what that might spell for treating other brain diseases beyond pain.
Source: Tulane University
