February 17, 2014
Groundbreaking research has unlocked the mystery of sodium’s impact on opioid receptors, offering hope for the future development of medications targeting pain management and mood disorders.
Investigators from the University of North Carolina at Chapel Hill and the Scripps Research Institute in La Jolla, California, teamed up to understand how sodium affects the delta-opioid receptor, a puzzle long studied but impossible to solve because of inadequate imaging technology.
In recent years, however, pioneering research at Scripps created the sharpest resolution of a crystallized delta-opioid receptor to date, which provided the first atomic-level look at how amino acids hold a sodium ion in the middle of the receptor, impacting how it interacts with neurotransmitter peptides. A research team at UNC then created new versions of the receptor that contained mutant sodium-site amino acids to determine how sodium altered the receptor’s signaling.
Sodium is essential to life and almost any biological process in cells, explained study co-author Dr. Patrick Giguere, a research associate at UNC. He said studying sodium is extremely challenging because it can’t be removed without disrupting other biological processes or killing the cell itself.
“One of the only ways is to use indirect pathways,” he continued. “We could view the crystal structure at the atomic level, so we were able to design specific mutations of the receptor that disrupted attraction with the sodium without removing sodium from the environment.”
Dr. Giguere said they discovered a novel cavity within the heart of the receptor that plays a fundamental role in directing and polarizing cell signaling. “We believe this cavity is suitable for the development of novel allosteric or bitopic drugs,” he added.
According to Dr. Giguere, the research team was surprised to discover that sodium affects only a single, specific pathway that’s been shown in animal models to have therapeutic potential for depression, Parkinson’s disease, and pain and mood disorders.
The problem, said Dr. Giguere, is that current drugs targeting the pathway can cause significant side effects, particularly epileptic seizures in patients who take opioids to manage chronic pain. But, he continued, understanding how sodium and the delta-opioid receptor interact could further research aimed at determining how other opioid receptors work, which could lead to the development of more targeted therapies for brain-related conditions that won’t cause adverse effects.
The study was published online in the journal Nature.
1. Fenalti G, Giguere PM, Katritch V, et al. Molecular control of δ-opioid receptor signaling. Nature. 2014 Jan 12. [Epub ahead of print]