Medical researchers have uncovered how salt acts a "key regulator" for drugs used to treat brain conditions such as Parkinson's disease and depression.
This new research could open up the door for the creation of better medicines with fewer side effects, a University of North Carolina School of Medicine news release reported.
"There's a reason why certain drugs, for instance, work well for some people but not others and why those drugs can cause serious side effects, such as seizures, addiction, and death due to overdose," Patrick Giguere, PhD, co-first author of the paper and UNC pharmacology postdoctoral fellow, said. "The reason is that we haven't known the precise biological markers for those drugs."
Markers are "the biological abnormalities that drugs aim to treat," the news release reported. Drugs such as morphine and oxycodone (not to mention heroin) target opioid receptors, which use a number of pathways to get their chemical signals to the brain.
"These drugs activate all of the receptor pathways," Giguere said. "None of them modulates just one pathway."
The fact that opioid receptors can target almost any receptor pathway could be related to the negative side effects they impose.
The researchers figured out how to modulate only one pathway. By "tweaking" certain amino acids ("building blocks of receptors"), the team was able to manipulate the way "opioid receptors control chemical signals."
Forty years ago scientists discovered if they altered the sodium (an element of table salt) levels in the brain it altered the behavior of opioid receptors. Since there was no technology available that allowed researchers to get a clear picture of the receptor to see how the sodium was behaving, there was no way for them to determine why this phenomenon occurred.
Two years ago scientists created a high-resolution crystal structure of the delta-opioid receptor that changed everything. The team created this structure out of a protein using x-rays and liquid nitrogen. The crystal allowed the researchers to peer inside the receptor and the sodium within.
"Sodium is not everywhere in the receptor," Giguere said. "It fits in a pocket within the receptor's structure."
The team worked to uncover how different amino acids "hold the sodium ion in place" they interact with the ion to modulate brain signals.
"The amino acids control the sodium ion," Giguere said. "This control is like a trigger; it has a specific function on the opioid receptor."
When the researchers mutated the amino acids they saw a dramatic change in behavior from the opioid receptors and how they reacted to certain chemical signals.
In one case the team "tweaked an amino acid to cause a major change in the signaling response of the receptor's beta-arrestin pathway, which is responsible for shutting down chemical signaling," the news release reported.
These results suggests scientists could effectively create a drug that responds to only the desired pathways. Today's medications are only able to switch opioid receptor on or off; this new method allows them to "fine tune" it.
"This is a new field of research, which we call functional selectivity," Giguere said. "There are very few crystal structures that show how this sort of pathway selectivity can work. This is why we think our findings will lead to another, potentially better class of drugs."
