Cell adhesion molecule close homolog of L1 binds to the dopamine receptor D2 and inhibits the internalization of its short isoform

Cell adhesion molecule close homolog of L1 (CHL1) and the dopamine receptor D2 (DRD2) are associated with psychiatric and mental disorders. We here show that DRD2 interacts with CHL1 in mouse brain, as evidenced by co‐immunostaining, proximity ligation assay, co‐immunoprecipitation, and pull‐down assay with recombinant extracellular CHL1 domain fused to Fc (CHL1‐Fc). Direct binding of CHL1‐Fc to the first extracellular loop of DRD2 was shown by ELISA. Using HEK cells transfected to co‐express CHL1 and the short (DRD2‐S) or long (DRD2‐L) DRD2 isoforms, co‐localization of CHL1 and both isoforms was observed by immunostaining and proximity ligation assay. Moreover, CHL1 inhibited agonist‐triggered internalization of DRD2‐S. Proximity ligation assay showed close interaction between CHL1 and DRD2 in neurons expressing dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa (DARPP32) or tyrosine hydroxylase (TH) in tissue sections of adult mouse striatum. In cultures of striatum or ventral midbrain, CHL1 was also closely associated with DRD2 in DARPP32‐ or TH‐immunopositive cells, respectively. In the dorsal striatum of CHL1‐deficient mice, lower levels of DRD2 and phosphorylated TH were observed, when compared to wild‐type littermates. In the ventral striatum of CHL1‐deficient mice, levels of phosphorylated DARPP32 were reduced. We propose that CHL1 regulates DRD2‐dependent presynaptic and postsynaptic functions.