A New Frontier in Neuroscience: How Tulane University Researchers Uncovered a Hidden Pathway of Neuronal Communication
A groundbreaking discovery by researchers at Tulane University, in collaboration with eight leading institutions, has opened a new chapter in the understanding of neuronal communication and pain signaling. This research, published in Science, identifies a previously unknown mechanism by which nerve cells transmit messages—one that could revolutionize pain treatment and deepen our understanding of learning and memory. The findings suggest that neurons communicate not only through traditional synaptic pathways but also by releasing enzymes into the extracellular environment. This discovery holds the potential to simplify drug development and provide safer therapeutic options for patients experiencing chronic or post-surgical pain.
The study was co-led by Matthew Dalva, director of the Tulane Brain Institute and professor of cell and molecular biology, and Ted Price, director of the Center for Advanced Pain Studies at the University of Texas at Dallas. Together with teams from several top-tier research institutions, they uncovered a signaling process that may be central to both pain sensation and synaptic plasticity. Their work focuses on an enzyme known as vertebrate lonesome kinase (VLK), which appears to operate outside the cell—contrary to the long-held belief that phosphorylation, a biochemical process involving the addition of phosphate groups, operates solely inside cells.
A Newly Discovered Mode of Neuronal Communication
Traditionally, scientists have believed that neurons communicate through a combination of electrical impulses and chemical signaling across synapses. However, the Tulane-led team has uncovered an entirely new signaling modality. Neurons, they found, can release an enzyme—specifically VLK—into the extracellular space, where it modifies proteins on nearby cells. This modification triggers pain pathways and alters neuronal communication without entering the cell itself.
“This finding changes our fundamental understanding of how neurons communicate,” Dalva explained. According to him, the team discovered that the released enzyme can activate pain signaling by modifying exterior cell-surface proteins. Remarkably, this activation occurs without altering normal movement or sensory functions, suggesting that VLK selectively influences pain pathways.
This is a profound shift in the scientific understanding of cell communication. For decades, phosphorylation was considered an intracellular process, confined to the internal workings of a cell. Demonstrating that phosphorylation can occur outside cells broadens the known biological toolkit for intercellular communication and opens up new avenues for medical intervention.
VLK’s Role in Pain, Learning, and Memory
One of the most striking discoveries in the study is that VLK directly influences a receptor involved in pain, learning, and memory. The release of this enzyme increases activation of this receptor, amplifying pain responses. In mouse models, researchers observed that removing VLK from pain-sensitive neurons prevented the animals from experiencing typical post-surgical pain. Importantly, their normal movements and sensory abilities remained unchanged. This specificity suggests that VLK is part of a finely tuned mechanism for pain signaling, and blocking it could bring pain relief without disrupting essential neural functions.
Price noted that the study touches on foundational aspects of synaptic plasticity—the process by which connections between neurons strengthen or weaken over time. This process underlies learning and memory. Since the same receptors influenced by VLK are involved in these cognitive functions, understanding how VLK modifies neuronal communication could help explain the shared molecular pathways between pain and memory.
This dual role underscores the complexity of the nervous system. Pain, learning, and memory often appear interconnected, and this study provides new molecular evidence to support this relationship. It paves the way for future research into how these seemingly distinct processes share overlapping biological mechanisms.
Implications for Drug Development
Perhaps one of the most transformative aspects of the study is its implications for drug design. Many current neurological drugs must penetrate the cell membrane to reach their target molecules. This complicates drug development and increases the risk of side effects, as these drugs often disrupt essential intracellular functions. Dalva emphasized that targeting enzymes like VLK, which operate outside the cell, could simplify drug design and reduce unintended effects.
This extracellular mechanism offers a new therapeutic strategy: instead of blocking internal pathways such as NMDA receptors—known to cause serious side effects when inhibited—future drugs could modulate VLK activity from outside the cell. This approach may lead to safer treatments for chronic pain, learning impairments, and neurodegenerative disorders.
Moreover, the discovery that phosphorylation can control extracellular interactions is one of the first of its kind. It challenges the traditional assumption that effective drug targets must lie within the cell. If extracellular phosphorylation proves to be widespread, this research could reshape how pharmaceutical scientists conceptualize drug design for neurological diseases.
A Large Collaborative Effort
The complexity of this discovery reflects the scale of the collaborative effort behind it. Tulane University worked alongside institutions such as the University of Texas Health Science Center at San Antonio, MD Anderson Cancer Center, Princeton University, NYU Grossman School of Medicine, and others. This broad team provided a multidisciplinary approach, combining expertise in synaptic biology, pain research, molecular signaling, and protein chemistry.
Dalva acknowledged that the findings emerged from this extensive collaboration. Each institution contributed specialized knowledge and experimental methods, enabling a comprehensive investigation of VLK’s properties and functions. Co-first authors Dr. Sravya Kolluru, Dr. Praveen Chander, and Dr. Kristina Washburn from Tulane’s Dalva Lab played critical roles in advancing the project.
Funding from major U.S. research groups—including the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse, and the National Center for Research Resources—underscored the importance of investigating novel pain mechanisms and neurological pathways.
Future Directions and Broader Impacts
While this research marks a major breakthrough, many questions remain. Researchers plan to determine whether VLK acts on only a narrow group of proteins or if it plays a broader role in neural communication. If extracellular phosphorylation turns out to be a widespread phenomenon, it could reshape the scientific understanding of cell biology beyond neuroscience.
The findings also hold potential for developing treatments for a wide range of neurological disorders, not just pain. If VLK influences learning and memory pathways, modulating its activity might offer new therapeutic routes for conditions involving cognitive decline, dementia, or impaired neural plasticity.
In summary, the discovery of an extracellular signaling enzyme like VLK represents a paradigm shift in neuroscience. It opens unexplored territory in both basic biological science and applied medicine. By revealing a novel form of neuron-to-neuron communication, this research not only expands scientific knowledge but also offers real hope for safer, more effective neurological treatments in the future.
Story Source: Tulane University.
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