Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

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
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 2,800+ scientific posters on ePosters
  • More than 4,000+ 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 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

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
TSRI, UC San Diego Launch 'Virtual Cell' Project
Drawing on complementary strengths of two San Diego institutions, The Scripps Research Institute (TSRI) and the University of California, San Diego (UC San Diego) have formed a new consortium with a big mission: to map cells in space and time.
Monday, September 21, 2015
Scripps Scientists Awarded NIH Grant for Biomarker Studies
$2.3 million grant awarded to develop new diagnostics for cancer, rheumatoid arthritis, colitis.
Tuesday, May 06, 2014
Scientists Discover a New Type of Protein Modification that May Play a Role in Cancer and Diabetes
Scientists at The Scripps Research Institute (TSRI) have discovered a new type of chemical modification that affects numerous proteins within mammalian cells.
Tuesday, August 06, 2013
Chemists Devise Inexpensive, Benchtop Method for Marking and Selecting Cells
Chemists at The Scripps Research Institute have found an easier way to perform one of the most fundamental tasks in molecular biology.
Wednesday, January 16, 2013
Scientists Discover How Two Proteins Help Keep Cells Healthy
The work has implications for cancer drug development.
Thursday, December 06, 2012
Team Reveals Key Protein Interactions Involved in Neurodegenerative Disease
New study reveals the structure of c-jun-N-terminal kinases (JNK) enzymes.
Thursday, November 15, 2012
Scientists Find Structure of a Protein that Makes Cancer Cells Resistant to Chemotherapy
A research team at the Scripps Research Institute has obtained the first glimpse of a protein that keeps certain substances, including many drugs, out of cells.
Monday, March 30, 2009
Scientific News
Non-Disease Proteins Kill Brain Cells
Scientists at the forefront of cutting-edge research into neurodegenerative diseases such as Alzheimer’s and Parkinson’s have shown that the mere presence of protein aggregates may be as important as their form and identity in inducing cell death in brain tissue.
Closing the Loop on an HIV Escape Mechanism
Research team finds that protein motions regulate virus infectivity.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Gut Microbes Signal to the Brain When They're Full
Don't have room for dessert? The bacteria in your gut may be telling you something.
Turning up the Tap on Microbes Leads to Better Protein Patenting
Mining millions of proteins could become faster and easier with a new technique that may also transform the enzyme-catalyst industry, according to University of California, Davis, researchers.
Exploring the Causes of Cancer
Queen's research to understand the regulation of a cell surface protein involved in cancer.
Measuring microRNAs in Blood to Speed Cancer Detection
A simple, ultrasensitive microRNA sensor holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.
Novel Proteins Linked to Huntington's Disease
University of Florida Health researchers have made a new discovery about Huntington's disease, showing that the gene that causes the fatal disorder makes an unexpected "cocktail" of mutant proteins that accumulate in the brain.
Enzyme Critical to Maintaining Telomere Length Discovered
New method expected to speed understanding of short telomere diseases and cancer.
New Method Identifies Up to Twice as Many Proteins and Peptides
An international team of researchers developed a method that identifies up to twice as many proteins and peptides in mass spectrometry data than conventional approaches.
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
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos