CASPR 2 forms a complex with GPR 37 via MUPP 1 but not with GPR 37(R558Q), an autism spectrum disorder‐related mutation

Autism spectrum disorder ( ASD ) is a developmental brain disorder. Mutations in synaptic components including synaptic adhesion molecules have been found in ASD patients. Contactin‐associated protein‐like 2 ( CASPR 2) is one of the synaptic adhesion molecules associated with ASD . CASPR 2 forms a complex with receptors via interaction with multiple PDZ domain protein 1 ( MUPP 1). Little is known about the relationship between impaired CASPR 2‐ MUPP 1‐receptor complex and the pathogenesis of ASD . GPR 37 is a receptor for survival factors. We recently identified mutations including R558Q in the G‐protein‐coupled receptor 37 ( GPR 37 ) gene in ASD patients. The mutated GPR 37s accumulate in the endoplasmic reticulum. In this study, we show that GPR 37 is a component of the CASPR 2‐ MUPP 1 receptor complex in the mouse brain. CASPR 2 and GPR 37 mainly interacted with the PDZ 3 and PDZ 11 domains of MUPP 1, respectively. Compared to GPR 37, GPR 37(R558Q) slightly interacted with MUPP 1 and caused dendritic alteration. GPR 37, but not GPR 37(R558Q) nor GPR 37‐deltaC which lacks its PDZ binding domain, was transported to the cell surface by MUPP 1. In primary hippocampal neurons, GPR 37 co‐localized with MUPP 1 and CASPR 2 at the synapse, but not GPR 37(R558Q). Thus, ASD ‐related mutation of GPR 37 may cause the impaired CASPR 2‐ MUPP 1‐ GPR 37 complex on the dendrites associated with one of the pathogenesis of ASD .In this study, we identified that GPR37 is a component of the MUPP1 and CASPR2 receptor complex. Autism deleterious mutated GPR37(R558Q) slightly interacts with MUPP1 and retains in ER, resulting in dendritic alteration. In neuron, GPR37, but not GPR37(R558Q), is transported to the dendrite and synapse by MUPP1. Thus, ASD‐related mutation of GPR37 may cause the impaired CASPR2‐MUPP1‐GPR37 complex on the dendrites associated with one of the pathogenesis of ASD.