It took scientists 40 years to unlock the mysterious effect sodium has on key brain cell receptors.
They have now discovered how sodium influences the signalling of opioid receptors - a major class of brain cell receptors - paving the way for new therapies to treat a host of brain-related conditions.
"It opens the door to understand opioid-related drugs to treat pain and mood disorders, among others," said lead author Gustavo Fenalti, a postdoctoral fellow at The Scripps Research Institute (TSRI) in California, US.
"This discovery has helped us decipher a 40-year-old mystery about sodium's control of opioid receptors," said pharmacologist Professor Bryan Roth from University of North Carolina.
"It is amazing to know how sodium sits right in the middle of the receptor as a co-factor or allosteric modulator," Roth said in the study that appeared in the journal Nature.
The team constructed a novel version of one of the main opioid receptors in the human brain, known as the delta opioid receptor.
After X-ray crystallography, they revealed the receptor's 3D atomic structure to a very high resolution.
"Such a high resolution was really necessary to be able to understand in detail how the receptor works," said Stevens.
The slipped in a sodium ion in the opioid receptor. 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.
They found that certain amino-acid changes cause radical shifts in the receptor's normal signalling response.
In practical terms, these findings suggests a number of ways in which new drugs could target these receptors, said the study.
Opioid receptors are activated by peptide neurotransmitters in the brain.
They can also be activated by plant-derived and synthetic drugs that mimic these peptides - like morphine, codeine, oxycodone and heroin.
Sodium is best known to biologists as one of the key 'electrolytes' needed for the basic workings of cells.