Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Scientists Solve 40-year Mystery of How Sodium Controls Opioid Brain Signaling

Published: Thursday, January 16, 2014
Last Updated: Thursday, January 16, 2014
Bookmark and Share
The findings pave way for new therapies for treating pain and mood disorders.

Scientists have discovered how the element sodium influences the signaling of a major class of brain cell receptors, known as opioid receptors. The discovery, from The Scripps Research Institute (TSRI) and the University of North Carolina (UNC), suggests new therapeutic approaches to a host of brain-related medical conditions.

“It opens the door to understanding opioid related drugs for treating pain and mood disorders, among others,” said lead author Dr. Gustavo Fenalti, a postdoctoral fellow in the laboratory of Professor Raymond C. Stevens of TSRI’s Department of Integrative Structural and Computational Biology.

“This discovery has helped us decipher a 40-year-old mystery about sodium’s control of opioid receptors,” said Stevens, who was senior author of the paper with UNC pharmacologist Professor Bryan Roth. “It is amazing how sodium sits right in the middle of the receptor as a co-factor or allosteric modulator.”

The findings appear in an advanced online publication in the journal Nature on January 12, 2014.

A Sharper Image

The researchers revealed the basis for sodium’s effect on signaling with a high-resolution 3-D view of an opioid receptor’s atomic structure. Opioid receptors are activated by peptide neurotransmitters (endorphins, dynorphins and enkephalins) in the brain. They can also be activated by plant-derived and synthetic drugs that mimic these peptides: among them morphine, codeine, oxycodone and heroin.

Despite these receptors’ crucial importance in health and disease, including pain disorders and addictions, scientists have only begun to understand in detail how they work. Opioid receptors are inherently flimsy and fragile when produced in isolation, and thus have been hard to study using X-ray crystallography, the usual structure-mapping method for large proteins.

In recent years, the Stevens laboratory has helped pioneer the structure determination of G protein-coupled receptors. Although the first crystallographic structures of opioid receptors were determined in 2012, these structural models weren’t fine-grained enough to solve a lingering mystery, particularly for the human delta opioid receptor.

That mystery concerned the role of sodium. The element is perhaps best known to biologists as one of the key “electrolytes” needed for the basic workings of cells. In the early 1970s, researchers in the laboratory of neuroscientist Solomon Snyder at Johns Hopkins University, who had helped discover opioid receptors, found evidence that sodium ions also act as a kind of switch on opioid receptor signaling. They noted that at concentrations normally found in brain fluid, these ions reduced the ability of opioid peptides and drugs like morphine to interact with opioid receptors.

How sodium could exert this indirect (“allosteric”) effect on opioid receptor activity was unclear—and has remained an unsolved puzzle for decades. Now that scientists have discovered the mechanism of sodium’s effect, then in principle they can exploit it to develop better opioid-receptor-targeting drugs.

A Switch Controlling Pain, Depression and Mood Disorders

For the new study, the team constructed a novel, fusion-protein-stabilized version of one of the main opioid receptors in the human brain, known as the delta opioid receptor, and managed to form crystals of it for X-ray crystallography. The latter revealed the receptor’s 3-D atomic structure to a resolution of 1.8 Angstroms (180 trillionths of a meter)-the sharpest picture yet of an opioid receptor.

“Such a high resolution is really necessary to be able to understand in detail how the receptor works,” said Stevens.

The analysis yielded several key details of opioid receptor structure and function, most importantly the details of the “allosteric sodium site,” where a sodium ion can slip in and modulate receptor activity.

The team was able to identify the crucial amino acids that hold the sodium ion in place and transmit its signal-modulating effect. “We found that the presence of the sodium ion holds the receptor protein in a shape that gives it a different affinity for its corresponding neurotransmitter peptides,” Fenalti said.

With the structural data in hand, the researchers designed new versions of the receptor, in which key sodium-site amino-acids were mutated, to see how this would affect receptor signaling. Co-lead author Research Associate Patrick M. Giguere and colleagues in Roth’s Laboratory at UNC, which has long collaborated with the Stevens laboratory, tested these mutant receptors and found that certain amino-acid changes cause radical shifts in the receptor’s normal signaling response.

The most interesting shifts involved a little-understood secondary or “alternative” signaling route, known as the beta-arrestin pathway, whose activity can have different effects depending on the type of brain cell involved. Some drugs that normally bind to the delta opioid receptor and have little or no effect on the beta-arrestin pathway turned out to strongly activate this pathway in a few of these mutant receptors.

In practical terms, these findings suggests a number of ways in which new drugs could target these receptors—and not only delta opioid receptors but also the other two “classical” opioid receptors, mu and kappa opioid receptors. “The sodium site architecture and the way it works seems essentially the same for all three of these opioid receptor types,” said Fenalti.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More Than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Memory Suppressor Gene Identified
Scientists have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, a widely recognized substitute for human memory studies.
Tuesday, April 19, 2016
Promising Results for AIDS Vaccine
Engineered vaccine protein binds key immune cells that exist in nearly everyone.
Wednesday, March 30, 2016
New Targets for Diabetes, Inflammation Discovered
The Scripps Research Institute and Salk Scientists discover 'outlier' enzymes that could offer new targets to treat diabetes and inflammation.
Tuesday, March 29, 2016
Versatile New Molecule-Building Technique
Chemists at The Scripps Research Institute (TSRI) have devised a new and widely applicable technique for building potential drug molecules and other organic compounds.
Tuesday, January 19, 2016
Flipping Molecular 'Switch' May Reduce Nicotine's Effects in the Brain
Scientists at The Scripps Research Institute (TSRI) have discovered that a lipid (fat molecule) in brain cells may act as a “switch” to increase or decrease the motivation to consume nicotine.
Friday, January 15, 2016
TSRI Team Comes Together with Rare Disease Community
Don’t worry, science fiction fans, the machines aren’t taking over quite yet. It turns out humans still beat computers at reading and comprehending text.
Monday, January 11, 2016
Single ‘Transformer’ Proteins
A new study led by scientists at The Scripps Research Institute (TSRI) and St. Jude Children’s Research Hospital shows how a protein involved in cancer twists and morphs into different structures.
Monday, January 11, 2016
Pushing Drug Discovery Forward
A new study, led by scientists at The Scripps Research Institute (TSRI), shows how different pharmaceutical drugs hit either the “on” or “off” switch of a signaling protein linked to asthma, obesity and type 2 diabetes.
Monday, December 14, 2015
TSRI Team Finds Unique Anti-Diabetes Compound
Scientists from The Scripps Research Institute (TSRI) have deployed a powerful new drug discovery technique to identify an anti-diabetes compound with a novel mechanism of action.
Thursday, December 10, 2015
Protein 'Talks' to Wrong Partners in Cystic Fibrosis
Scientists at The Scripps Research Institute (TSRI) have found evidence that a mutant protein responsible for most cases of cystic fibrosis is so busy “talking” to the wrong cellular neighbors that it cannot function normally and is prematurely degraded.
Monday, December 07, 2015
'Fingerprints' for Major Drug Development Targets
For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have created detailed “fingerprints” of a class of surface receptors that have proven highly useful for drug development.
Friday, December 04, 2015
Potential Treatment for Life-Threatening Viral Infections Revealed
The findings point to new therapies for Dengue, West Nile and Ebola.
Thursday, November 26, 2015
Surprising Trait Found in Anti-HIV Antibodies
Scientists at The Scripps Research Institute (TSRI) have new weapons in the fight against HIV.
Monday, November 23, 2015
Potential Persistent Tuberculosis Treatment
Researchers have discovered several first-in-class compounds that target hidden TB infections by attacking a critical process the bacteria use to survive in the hostile environment of the lungs.
Monday, November 23, 2015
Long-Sought Protein Sensor for the ‘Sixth Sense’ Discovered
In a study led by scientists from The Scripps Research Institute (TSRI)the sensor protein for propioception has been identified.
Monday, November 16, 2015
Scientific News
How Skeletal Stem Cells Form The Blueprint Of The Face
USC researchers discover that two types of molecular signals work to control where and when stem cells turn into facial cartilage.
Ketamine Metabolism Lifts Depression
NIH-funded team finds rapid-acting, non-addicting agent in mouse study.
Faster, Cheaper Way to Produce New Antibiotics
A novel way of synthesising a promising new antibiotic has been identified by scientists at the University of Bristol.
Process Contaminants in Vegetable Oils and Foods
Glycerol-based process contaminants found in palm oil, but also in other vegetable oils, margarines and some processed foods, raise potential health concerns for average consumers of these foods in all young age groups, and for high consumers in all age groups.
Improving Natural Killer Cancer Therapy
Vanderbilt University researchers discover transcription factor critical for NK cell expansion. Findings could lead to increased therapeutic efficacy.
Molecular Mechanism For Generating Specific Antibody Responses Discovered
Study could spur more ways to treat autoimmune disease, develop accurate vaccines.
Monovar Drills Down Into Cancer Genome
Rice, MD Anderson develop program to ID mutations in single cancer cells.
It’s Now Easier To Go With The Flow
Rice University tool simplifies comparison of flow cytometry data for laboratories.
Autism, Cancer Share a Remarkable Number of Risk Genes
Researchers with the UC Davis Comprehensive Cancer Center, MIND Institute identify more than 40 common genes.
Number Of Known Genetic Risk Factors For Endometrial Cancer Doubled
An international collaboration of researchers has identified five new gene regions that increase a woman’s risk of developing endometrial cancer, one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!