ABSTRACT
Stress and anxiety disorders are risk factors for depression and these behaviors are modulated by corticotrophin-releasing factor receptor 1 (CRFR1) and serotonin receptor (5-HT(2)R). However, the potential behavioral and cellular interaction between these two receptors is unclear. We found that pre-administration of corticotrophin-releasing factor (CRF) into the prefrontal cortex of mice enhanced 5-HT(2)R-mediated anxiety behaviors in response to 2,5-dimethoxy-4-iodoamphetamine. In both heterologous cell cultures and mouse cortical neurons, activation of CRFR1 also enhanced 5-HT(2) receptor-mediated inositol phosphate formation. CRFR1-mediated increases in 5-HT(2)R signaling were dependent on receptor internalization and receptor recycling via rapid recycling endosomes, resulting in increased expression of 5-HT(2)R on the cell surface. Sensitization of 5-HT(2)R signaling by CRFR1 required intact PDZ domain-binding motifs at the end of the C-terminal tails of both receptor types. These data suggest a mechanism by which CRF, a peptide known to be released by stress, enhances anxiety-related behavior via sensitization of 5-HT(2)R signaling.
Subject(s)
Anxiety/metabolism , Receptors, Corticotropin-Releasing Hormone/physiology , Receptors, Serotonin, 5-HT2/metabolism , Signal Transduction/physiology , Amphetamines/pharmacology , Animals , Anxiety/drug therapy , Anxiety/physiopathology , Behavior, Animal/drug effects , Behavior, Animal/physiology , Biotinylation/methods , Cells, Cultured , Corticotropin-Releasing Hormone/pharmacology , Cyclic AMP/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Embryo, Mammalian , Fluorobenzenes/pharmacology , Hormones/pharmacology , Humans , Inositol Phosphates/metabolism , Ionophores/pharmacology , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Monensin/pharmacology , Mutation/genetics , Neurons , Piperidines/pharmacology , Prefrontal Cortex/cytology , Rats , Reaction Time/drug effects , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Serotonin, 5-HT2/genetics , Serotonin/pharmacology , Serotonin 5-HT2 Receptor Agonists , Serotonin 5-HT2 Receptor Antagonists , Serotonin Agents/pharmacology , Signal Transduction/drug effects , TransfectionABSTRACT
The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.
