By finding how sodium influences a major call of brain cell receptors, scientists speculate that this revelation may pave way for development of new treatments for brain disorders.
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, said that this discovery has helped them decipher a 40-year-old mystery about sodium's control of opioid receptors.
AdvertisementThe 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 and also by plant-derived and synthetic drugs mimicking these peptides: among them morphine, codeine, oxycodone and heroin.
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.
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.
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 findings have been published online in the journal Nature.