The 5-HT4 receptor interacts with adhesion molecule L1 to modulate morphogenic signaling in neurons

ABSTRACT Morphological remodeling of dendritic spines is critically involved in memory formation and depends on adhesion molecules. Serotonin receptors are also implicated this remodeling, though the underlying mechanisms remain enigmatic. Here, we uncovered a signaling pathway involving molecule L1CAM (L1) serotonin receptor 5-HT4 (5-HT4R, encoded by HTR4). Using Förster resonance energy transfer (FRET) imaging, demonstrated physical interaction between 5-HT4R L1, found that 5-HT4R–L1 heterodimerization facilitates mitogen-activated protein kinase activation Gs-dependent manner. We 5-HT4R–L1-mediated G13-dependent modulation cofilin-1 activity. In hippocampal neurons vitro, triggers maturation spines. Thus, module represents previously unknown molecular regulating synaptic remodeling.