X11 and X11‐like proteins regulate the level of extrasynaptic glutamate receptors.

X11/Mint 1 and X11‐like (X11L)/Mint 2 are neuronal adaptor protein to regulate trafficking and/or localization of various membrane proteins. By analyzing the localization of neuronal membrane proteins in X11‐, X11L‐, and X11/X11L doubly deficient mice with membrane fractionation procedures, we found that deficient of X11 and X11L decreased the level of glutamate receptors in non‐PSD fraction. This finding suggests that X11 and X11L regulate the glutamate receptor micro‐localization to the extrasynaptic region. In vitro coimmunoprecipitation studies of NMDA receptors lacking various cytoplasmic regions with X11 and X11L proteins harboring domain deletion suggest that extrasynaptic localization of NMDA receptor may be as a result of the multiple interactions of the receptor subunits with X11 and X11L regulated by protein phosphorylation, while that of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor subunits is not dependent on the binding with X11 and X11L proteins. Because the loss of X11 and X11L tends to impair the exocytosis, but not endocytosis, of glutamate receptors, NMDA receptors are likely to be supplied to the extrasynaptic plasma membrane with a way distinct from the mechanism regulating the localization of NMDA receptors into synaptic membrane region. Reduced localization of NMDA receptor into the extrasynaptic region increased slightly the phosphorylation level of cAMP responsible element binding protein in brain of X11/X11L doubly deficient mice compare to wild‐type mice, suggesting a possible role of X11 and X11L in the regulation of signal transduction pathway through extrasynaptic glutamate receptors. Open science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. X11 and X11L are neuronal adaptor protein to regulate trafficking and localization of various membrane proteins, but their functions remain controversial for glutamate receptors. We found that deficient of X11 and X11L decreased the level of NMDA receptors at extrasynaptic region. X11 and X11L associate NMDA receptors through their multiple interactions and the association is regulated by protein phosphorylation. This mechanism is thought to be distinct from the mechanism regulating the localization of NMDA receptors into synaptic membrane region. Because the level of extrasynaptic NMDA receptors influences in the proapoptotic signal transduction, our finding will contribute for understanding neurodegenerative disorders. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ [ABSTRACT FROM AUTHOR]