title: 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(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.
authors.affiliation: Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt (Main), Germany.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimokawa
authors.forename: Kaisa
authors.initials: K
authors.lastname: Haglund
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Caroline
authors.initials: C
authors.lastname: Grabbe
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kirkin
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoeller
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Qiu
authors.forename: Marina B
authors.initials: MB
authors.lastname: Londoño
authors.forename: Jun
authors.initials: J
authors.lastname: Ikezawa
authors.forename: Peter
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Birgit
authors.initials: B
authors.lastname: Stein
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Schwarzacher
authors.forename: David P
authors.initials: DP
authors.lastname: Wolfer
authors.forename: Nicole
authors.initials: N
authors.lastname: Ehrhardt
authors.forename: Rainer
authors.initials: R
authors.lastname: Heuchel
authors.forename: Ioannis
authors.initials: I
authors.lastname: Nezis
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Mirko H H
authors.initials: MHH
authors.lastname: Schmidt
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Oliver
authors.initials: O
authors.lastname: Bogler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D018491:Dopamine Agonists / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; C498782:Sh3kbp1 protein, mouse