Sodium key to opioid brain signalling

A high-resolution 3-D view of an opioid receptor’s atomic structure has resolved the 40-year mystery of how sodium controls opioid brain signalling. The structure was obtained by scientists at the Scripps Research Institute (TSRI) and University of North Carolina (UNC) and could open up avenues for therapeutic treatments for a range of brain-related medical conditions. “This discovery has helped us decipher a 40-year-old mystery about sodium’s control of opioid receptors,” said Professor Raymond C. Stevens, from TSRI. “It is amazing how sodium sits right in the middle of the receptor as a co-factor or allosteric modulator.” To obtain the structure, the team constructed a novel, fusion-protein-stabilised version of the delta opioid receptor – the main opioid receptor in the brain – and managed to form crystals of it for X-ray crystallography. The resulting structure was revealed to a resolution of 1.8 Angstroms – the sharpest picture yet of an opioid receptor. “Such high resolution is really necessary to be able to understand in detail how the receptor works,” said Stevens. Analysis revealed several key details about the receptor’s structure and function – particularly the allosteric sodium site, where a sodium ion can slip in and modulate receptor activity. The team also identified crucial amino acids that keep the sodium ion in place and transmits a signal-modulating effect. “We found that the presence of the sodium ion hold the receptor protein in a shape that gives it a different affinity for its corresponding neurotransmitter peptides,” said Dr Gustavo Fenalti, a post-doctoral fellow in Steven’s lab. Researchers then designed new versions of the receptor in which key sodium-site amino acids were mutated, which were tested in the lab of Professor Bryan Roth at UNC. They founds certain amino acid changes caused a radical shift in the receptor’s normal signalling response. The most interesting shift involved the beta-arrestin pathways, a secondary path whose activity can have different effects depending on the type of brain cell involved. Some drugs that usually bind to the delta opioid receptor and have little or no effect on the secondary pathway turned out to strongly activate the latter in a few mutant receptors. The findings – published in Nature – suggest a number of ways in which new drugs could target these receptors. Molecular control of delta-opioid receptor signalling