12 January 2006. There is a new link between serotonin and depression—it is a tiny protein of only 97 amino acids called p11. In the January 6 Science, Paul Greengard and colleagues at The Rockefeller University, New York, reported that p11 plays a key role in localizing 5-hydroxytryptmine 1B (5-HT1B) neuroreceptors to the cell surface, where they facilitate serotonergic transmission. Perhaps more importantly, the authors also report that levels of p11 are lower in brain samples taken from depressed patients, and that in animal models, tricyclic antidepressants or electroconvulsive therapy boosts levels of the protein in the brain. The findings could lead to a better understanding of the causes of depression, as well as point to more effective treatments, and may prove beneficial to the substantial number of schizophrenia patients who suffer from depression.
Most antidepressants work by increasing levels of serotonin, which is crucial for controlling mood. The specifics of serotonin’s role in depressed states have remained elusive, partly because there are at least 14 different types of serotonin receptor, each interacting with a plethora of other proteins that may have modulating effects. The 5-HT1B subtype is particularly interesting, however, because it is both an autoreceptor, appearing on neurons that make serotonin, and a heteroreceptor, found on projection neurons that are stimulated by serotonin-producing neurons. These are thought to modulate and facilitate, respectively, communication between neurons. 5-HT1B receptors have also been implicated in the pathology of a variety of psychiatric conditions, such as obsessive-compulsive disorder, anxiety, and aggression (see review by Moret and Briley, 2000).
In order to learn more about this receptor, first author Per Svenningsson and colleagues used the classic yeast two-hybrid screen to search for proteins that might bind to, and modulate, its activity. Using one of the intracellular loops of the receptor as “bait,” the authors fished out 29 clones, of which 26 turned out to harbor p11 cDNA. The interaction between the two proteins appears to be quite specific, because baits made from 5-HT1A, 5-HT2A, 5-HT5A, and 5-HT6 receptors, or baits using the dopamine D1 or D2 receptors, failed to attract the protein.
What affect might this small protein have on serotonin receptors? Clues to the role of p11 come from studies showing that it regulates translocation of transmembrane proteins to the cell surface. This may also be how it modulates 5-HT1B receptors, because when Svenningsson and colleagues transfected 5-HT1B-producing cells with p11 DNA, more of the serotonin receptors ended up at the cell membrane, and they appeared to be functional: 5-HT1B inhibits adenyl cyclase activity and in cells expressing p11, cyclic AMP production in response to forskolin was attenuated.
These data led the authors to examine the potential role of p11 in depression. They found modest though significant reductions in levels of p11 messenger RNA (15 percent lower) and protein (about 20 percent) in postmortem samples of anterior cingulate cortex from patients who had suffered from unipolar major depression. They also found that levels of the protein are markedly reduced in H/Rouen mice, a genetic model of depression. Furthermore, they found that p11 knockout mice had significantly fewer 5-HT1B receptors and exhibited a depressionlike phenotype, including decreased appetite, while animals overexpressing p11 behaved as if they were on antidepressants. In fact, when the authors used electroconvulsive therapy or administered the tricyclic antidepressant imipramine to mice, levels of p11 mRNA in the forebrain increased by 30 percent.
“Overall, this finding represents compelling evidence that p11 has a pivotal role in both the cause of depression and perhaps its successful treatment,” writes Trevor Sharp from the University of Oxford, England, in an accompanying Science perspective. In this regard, it might be worthwhile pursuing the development of drugs that can boost levels of p11. Of course, this would not necessarily represent a panacea for depression because other components of the serotonin signaling pathway, such as the serotonin transporter and other 5-HT receptors have also been implicated in the pathology of this condition (for a review, see Stockmeier, 2003).—Tom Fagan.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois J-M, Nomikos GG, Greengard P. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. January 6, 2006;311:77-80. Abstract