New research has found that an enzyme outside the cell itself is associated with pain. Scientists now want to make medicines that act on this enzyme and not directly on the cell, reducing side effects.
A new published in Science has identified a previously unknown nerve signaling mechanism that activates a “pain switch” outside the cell. The discovery could pave the way for a new class of safer, more targeted pain treatments.
Until then, the phosphorylation — the chemical process that cells use to regulate the activity of proteins — was studied and understood mainly inside the cell. Its role outside the cell, despite being observed on the external surface of many synaptic proteins, remained poorly understood. The research team sought to determine whether this external modification influences communication between neurons and whether such changes translate into differences in real-world behavior.
Their discoveries center on an enzyme called vertebrate solitary kinase (VLK). The researchers discovered that the active neurons release VLK in the space between nerve cells, where it modifies proteins involved in neural signaling. When VLK interacts with proteins on pain-sensitive neurons, it amplifies the activity of a pain receptor, ultimately activating a pain signaling switch from outside the cell.
Experiments in mice reinforced the crucial role of the enzyme. When scientists removed VLK from pain-sensitive neurons, the animals did not display the typical post-surgical pain responses, but still demonstrated normal movement and sensation. On the other hand, increased VLK levels intensified pain sensitivity, explains .
The discovery is particularly significant for the development of pain medications, an area long challenged by drugs that need to enter cells to block internal receptors, which causes many systemic side effects. Targeting external enzymes such as VLK could allow more precise and less risky interventions.
Matthew Dalva, a neuroscientist at Tulane University and senior author of the study, said the work “opens a new perspective on how to influence cellular behavior and, potentially, a simplest way to develop medicines that act externally, instead of having to penetrate the cell”.
