CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder‐related mutation

Abstract

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 (CASPR2) is one of the synaptic adhesion molecules associated with ASD. CASPR2 forms a complex with receptors via interaction with multiple PDZ domain protein 1 (MUPP1). Little is known about the relationship between impaired CASPR2-MUPP1-receptor complex and the pathogenesis of ASD. GPR37 is a receptor for survival factors. We recently identified mutations including R558Q in the G-protein-coupled receptor 37 (GPR37) gene in ASD patients. The mutated GPR37s accumulate in the endoplasmic reticulum. In this study, we show that GPR37 is a component of the CASPR2-MUPP1 receptor complex in the mouse brain. CASPR2 and GPR37 mainly interacted with the PDZ3 and PDZ11 domains of MUPP1, respectively. Compared to GPR37, GPR37(R558Q) slightly interacted with MUPP1 and caused dendritic alteration. GPR37, but not GPR37(R558Q) nor GPR37-deltaC which lacks its PDZ binding domain, was transported to the cell surface by MUPP1. In primary hippocampal neurons, GPR37 co-localized with MUPP1 and CASPR2 at the synapse, but not GPR37(R558Q). 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. 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.

The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons

“…CASK, which contains a calmodulin kinase domain and binds neurexin, is implicated in synaptic protein targeting (Hsueh, 2006). Caspr2 has been also reported to interact with MUPP1, which may play a role at the post-synapse (Krapivinsky et al, 2004;Tanabe et al, 2015). To our knowledge, none of these scaffolding proteins have been identified at the AIS and we were not able to detect MPP2 or CASK at this axonal sub-region using available commercial antibodies (data not shown).…”

“…We showed that deletion of each of these motifs decreases the AIS enrichment of the Caspr2 cytoplasmic tail reporter construct. Proteomic analysis had revealed that Caspr2 may interact with a set of scaffolding proteins including the MAGuKs MPP2 and CASK, and the multiple PDZ domain protein MUPP1 (Horresh Tanabe et al, 2015). Horresh et al also reported that the association of Caspr2 with MPP2 requires its 4.1B-and PDZbinding regions .…”

“…The cell surface expression of Caspr2 is regulated through an endocytosis motif that overlaps with the 4.1B-binding sequence (Bel et al, 2009). Caspr2 does not interact with type I PDZ proteins, like PSD-93, but may associate with MAGuK proteins of the MPP2 family and MUPP1 (also known as MPDZ) Tanabe et al, 2015). In the present study, we used deletion or chimeric constructs to identify cytoplasmic and extracellular determinants implicated in the AIS versus axonal distribution of Caspr2.…”

Mechanisms involved in the regulation of neuropeptide-mediated neurite outgrowth: a minireview

“…Complexity of the neuropeptide G protein-coupled cell receptors is thus enormous. Several studies have evidenced that GPCRs are involved in the pathogenesis of diseases ranging from Alzheimer to autism (Th athiah et al 2011;Tanabe et al 2015). Th ere are many theories dealing with the question that what level of regulation is crucial for the triggering of the pathogenic processes resulting in alterations of the neurite growth.…”

“…Moreover, extensive reviews on G protein subunits assembly and traffi cking have been published (Marrari et al 2007;Smrcka et al 2008). One study has demonstrated that mutation in G protein-coupled receptor 37 causes dendritic alterations in neurons (Tanabe et al 2015). Activated Gα, released from the plasma membrane traffi cs into the cytosol, regulates the microtubules stability via direct interaction with them (Yu et al 2009).…”