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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(Deltaex2)) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85(Deltaex2) 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(Deltaex2) mice.


Noriaki Shimokawa, Kaisa Haglund, Sabine M Hölter, Caroline Grabbe, Vladimir Kirkin, Noriyuki Koibuchi, Christian Schultz, Jan Rozman, Daniela Hoeller, Chun-Hong Qiu, Marina B Londoño, Jun Ikezawa, Peter Jedlicka, Birgit Stein, Stephan W Schwarzacher, David P Wolfer, Nicole Ehrhardt, Rainer Heuchel, Ioannis Nezis, Andreas Brech, Mirko H H Schmidt, Helmut Fuchs, Valerie Gailus-Durner, Martin Klingenspor, Oliver Bogler, Wolfgang Wurst, Thomas Deller, Martin Hrabé de Angelis, Ivan Dikic. CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice. The EMBO journal. 2010 Jul 21;29(14):2421-32

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PMID: 20551902

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