Premium
CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice
Author(s) -
Shimokawa Noriaki,
Haglund Kaisa,
Hölter Sabine M,
Grabbe Caroline,
Kirkin Vladimir,
Koibuchi Noriyuki,
Schultz Christian,
Rozman Jan,
Hoeller Daniela,
Qiu ChunHong,
Londoño Marina B,
Ikezawa Jun,
Jedlicka Peter,
Stein Birgit,
Schwarzacher Stephan W,
Wolfer David P,
Ehrhardt Nicole,
Heuchel Rainer,
Nezis Ioannis,
Brech Andreas,
Schmidt Mirko H H,
Fuchs Helmut,
GailusDurner Valerie,
Klingenspor Martin,
Bogler Oliver,
Wurst Wolfgang,
Deller Thomas,
de Angelis Martin Hrabé,
Dikic Ivan
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.120
Subject(s) - excellence , library science , marie curie , sociology , political science , law , european union , computer science , business , economic policy
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 Δex2 ) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85 Δex2 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 Δex2 mice.