CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice

Abstract

Despite extensive investigations of Cbl-interacting protein of 85 kDa (CIN85) in receptor trafficking and cytoskeletal dynamics, little is known about its functions in vivo. Here, we report the study of a mouse deficient of the two CIN85 isoforms expressed in the central nervous system, exposing a function of CIN85 in dopamine receptor endocytosis. Mice lacking CIN85 exon 2 (CIN85 Dex2 ) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85 Dex2 animals display abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum, an important centre for the coordination of animal behaviour. Importantly, CIN85 localizes to the post-synaptic compartment of striatal neurons in which it co-clusters with D2DRs. Moreover, it interacts with endocytic regulators such as dynamin and endophilins in the striatum. Absence of striatal CIN85 causes insufficient complex formation of endophilins with D2DRs in the striatum and ultimately decreased D2DR endocytosis in striatal neurons in response to dopamine stimulation. These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85 Dex2 mice.

Identification of Two Functionally Distinct Endosomal Recycling Pathways for Dopamine D2Receptor

“…For this reason, most antipsychotics currently in use are DRD2 antagonists. The function of DRD2 is determined by its levels on the plasma membrane (PM) (Lin et al, 2001Binda et al, 2002;Free et al, 2007;Kim et al, 2008a,b;Tirotta et al, 2008;Genedani et al, 2010), and DRD2 endocytosis plays an important role in its desensitization following DA stimulation (Kim et al, 2001;Jeanneteau et al, 2004;Kabbani et al, 2004;Macey et al, 2004;Namkung and Sibley, 2004;Sugiura et al, 2004;Bartlett et al, 2005;Genedani et al, 2005;Torvinen et al, 2005;Paspalas et al, 2006;Iizuka et al, 2007;Kim, 2008;Xiao et al, 2009;Celver et al, 2010;Shimokawa et al, 2010). However, the fate of DRD2 following DA-induced endocytosis remains controversial.…”

Significance of CIN85 Analysis in Nutritional Study

“…Interestingly, the CIN85 KO mice showed abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum [6], an important center for the coordination of animal behavior. Importantly, CIN85 localizes to the postsynaptic compartment of striatal neurons, in which it coclusters with D2DRs and with postsynaptic density protein 95 (PSD-95) [6], which is a scaffold protein involved in the assembly and function of the postsynaptic density complex [18].…”

“…Recently, we have found a novel function of CIN85 in the regulation of the signaling of behavior-related molecules [6]. To investigate the function of CIN85 in the central nervous system (CNS) in vivo, we generated mice deficient in the expression of two major CIN85 isoforms (CIN85-xl and CIN85-l) in the brain [6,16].…”

“…To investigate the function of CIN85 in the central nervous system (CNS) in vivo, we generated mice deficient in the expression of two major CIN85 isoforms (CIN85-xl and CIN85-l) in the brain [6,16]. By homologous recombination, we deleted exon 2 of the CIN85 genomic locus (CIN85 ∆ex2 ).…”

“…CIN85 controls the spatial and temporal assembly of multiprotein complexes that are involved in the regulation of cell growth, differentiation, migration, *Correspondence: Noriaki Shimokawa, Department of Nutrition, Takasaki University of Health and Welfare, 37-1 Nakaorui-machi, Takasaki-city, Gunma 370-0033, Japan, Tel: +81-27-352-1284 (ex. 7311); Fax: +81-27-353-2055; E-mail: shimokawa-n@takasaki-u.ac.jp Previously, we reported a novel in vivo function of CIN85 in the regulation of postsynaptic dopamine receptor endocytosis in striatal neurons [6]. Mice deficient in CIN85 (CIN85 Δex2 , lacking CIN85 exon 2, CIN85 KO mice) expression show the attention deficit / hyperactivity disorder (ADHD) phenotype.…”