Interaction between the close homolog of L1 and serotonin receptor 2c regulates signal transduction and behavior in mice

Abstract

The serotonergic system plays important roles in multiple functions of the nervous system and its malfunctioning leads to neurological and psychiatric disorders. Here, we show that the cell adhesion molecule close homolog of L1 (CHL1), which has been linked to mental disorders, binds to a peptide stretch in the third intracellular loop of the serotonin 2c (5-HT2c) receptor via its intracellular domain. Moreover, we provide evidence that CHL1 deficiency in mice leads to 5-HT2c receptor-related reduction in locomotor activity and reactivity to novelty and that CHL1 regulates signaling pathways triggered by constitutively active isoforms of the 5-HT2c receptor. Furthermore, we found that 5-HT2c receptor and CHL1 co-localize in striatal and hippocampal GABAergic neurons and that 5-HT2c receptor phosphorylation and association of phosphatase and tensin homolog (PTEN) and β-arrestin 2 with the 5-HT2c receptor is regulated by CHL1. Our results demonstrate that CHL1 regulates signal transduction pathways via constitutively active 5-HT2c receptor isoforms, thereby altering 5-HT2c receptor functions and implicating CHL1 as a novel modulator of the serotonergic system.