BioWorld International Correspondent
LONDON - The identification of a molecule that interacts with the neurotransmitter serotonin in the brain could provide clues to new ways of treating depression. The molecule, called p11, increases the number of a specific type of serotonin receptor on the surface of neurons.
Per Svenningsson, associate professor in neuropharmacology at the department of physiology and pharmacology at the Karolinska Institute in Stockholm, Sweden, told BioWorld International: "This protein regulates functions of the serotonin system and is down-regulated in depression-like states. Its discovery is important, because it increases our understanding of the pathophysiology of depression-like states."
An account of the studies leading to the discovery of p11 appears in the Jan. 6, 2006, issue of Science in a paper titled, "Alterations in 5-HT1B Receptor Function by p11 in Depression-Like States."
Commenting on the paper in a Perspectives article in the same issue ("A New Molecule to Brighten Mood"), Trevor Sharp, of the department of pharmacology at the University of Oxford in the UK, wrote: "Overall, this finding represents compelling evidence that p11 has a pivotal role in both the cause of depression and perhaps its successful treatment." He added that it "is now timely for translational science to take this exciting development to the next step."
Svenningsson and his colleagues at the Rockefeller University, of New York; the European Institute for Peptide Research, of Rouen, France; and Eli Lilly and Co., of Indianapolis, have been approached by biotech and pharmaceutical companies and are considering collaborations.
The starting point for the work in Science was the desire to know more about the 14 serotonin receptors that mediate the effects of antidepressant medications such as Prozac, which either alter the re-uptake of serotonin, or its metabolism. The group focused on the 5-HT1B group of receptors. Several studies already had suggested that the receptors play a role in obsessive-compulsive disorder, drug addiction, depression, anxiety, aggression and sleep.
Using a yeast two-hybrid screen - a technique that allowed them to identify any molecules that bound to 5-HT1B receptors - Svenningsson and his colleagues showed that the p11 protein bound specifically to that receptor.
The researchers found that p11 and 5-HT1B receptors precipitated out together in tests on cells and brain tissue; and in immunofluorescence studies, p11 and 5-HT1B receptors were found together on the cell surface.
When mice were given the antidepressant drug imipramine, tests showed that there was 30 percent more messenger RNA (mRNA) encoding p11 in their forebrains. That was not the case when the mice were given drugs other than antidepressants, such as Haloperidol, risperidone or diazepam. Repeated electroconvulsive therapy on the mice also increased amounts of p11 protein in their brains.
In another experiment, the researchers compared the amounts of p11 mRNA in the brains of mice that provide a genetic animal model of depression with those in the brains of mice without that genetic defect. They found that amounts of p11 mRNA, and of p11 protein itself, were "markedly reduced" in the genetic animal model of depression.
Similar checks on the postmortem brains of 15 people who had suffered from unipolar major depression disorder showed that they, too, had lower than normal levels of p11 mRNA and p11 protein.
Previous studies by others had shown that p11 has a role in moving certain types of ion channels to the cell surface. When Svenningsson and his team transfected cells with either 5-HT1B receptors and p11, or just with 5-HT1B receptors, they found that the cells transfected with p11 showed more 5-HT1B receptors at their surface than the cells transfected only with 5-HT1B receptors.
A further set of experiments evaluated the behavior of a transgenic mouse that overexpresses p11. The mice were generally more active and behaved as though they were treated with antidepressants, in a specific test for antidepressant efficacy.
The researchers also generated knockout mice that lacked functional p11. The mice were less responsive to stimulation of 5-HT1B receptors and showed a depression-like behavior.
Svenningsson said it was too early to say whether the p11 knockout mice could provide a new model for depression.
"What we can conclude at this point is that p11 appears to be a gene that is involved in the multiple complex changes that underlie depression," he said.
Next, the team plans to find out how p11 is regulated, and will search for additional proteins that play a similar role to p11.