Role of p11 in Cellular and Behavioral Effects of 5-HT4 Receptor Stimulation

Abstract

p11 (S100A10), a member of a large family of S100 proteins, interacts with serotonin receptor 1B (5-HTR1B), modulates 5-HT1B receptor signal transduction, and is required for antidepressant responses to activation of this receptor. In the current study, we investigated the specificity of the interaction between 5-HTR1B and p11 by screening brain-expressed S100 proteins against serotonin and noradrenergic receptors. The data indicate that p11 is unique among its family members for its interactions with defined serotonin receptors. We identify a novel p11-interacting receptor (5-HTR4) and characterize the interaction between p11 and 5-HTR4, demonstrating that (1) p11 and 5-HTR4 mRNA and protein are coexpressed in brain regions that are relevant for major depression, (2) p11 increases 5-HTR4 surface expression and facilitates 5-HTR4 signaling, and (3) p11 is required for the behavioral antidepressant responses to 5-HTR4 stimulation in vivo. The essential role played by p11 in modulating signaling through 5-HT4 as well as 5-HT1B receptors supports the concept that this protein may be a key determinant of vulnerability to depression.

Glucocorticoid Receptor and FKBP5 Expression Is Altered Following Exposure to Chronic Stress: Modulation by Antidepressant Treatment

“…It may be inferred that a reduction of its expression impairs the maintenance of cellular homeostasis under challenging conditions. With respect to p11, our data are in agreement with previous results showing that its expression is decreased in brain tissue of depressed individuals (Anisman et al, 2008;Svenningsson et al, 2006) as well as in an animal model of depression (Svenningsson et al, 2006), and that the p11 knockout (KO) mice have a depression-like phenotype (Svenningsson et al, 2006;Warner-Schmidt et al, 2009).…”

Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

“…p11, a member of the S100 family of proteins, is a key regulator of depressive-like states and antidepressant responses in rodent models (7)(8)(9). p11, also called S100A10, is a small acidic protein that interacts with specific serotonin receptors to regulate their trafficking and influence their localization at the cell surface (7,9).…”

Comorbidité entre la dépression et l’addiction

“…Ce système est aussi impliqué dans les comportements de récompense. Le laboratoire du Pr Paul Greengard a identifié la protéine p11 comme étant une petite protéine nécessaire à la localisation membranaire des récepteurs de la sérotonine 5HT1-B et 5HT4 [16,17]. Comme la quantité de p11 est inférieure dans le cerveau des patients dépressifs à celle du cerveau de sujets contrôles, ce laboratoire a créé une souris génétiquement invalidée pour le gène correspondant (p11-knocked-out) et a démontré que celle-ci présentait des comportements anhédoniques et de désespoir, interprétés comme des symptômes dépressifs [16].…”