CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice.
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.
Shimokawa
Noriaki
N
Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt (Main), Germany.
Haglund
Kaisa
K
Hölter
Sabine M
SM
Grabbe
Caroline
C
Kirkin
Vladimir
V
Koibuchi
Noriyuki
N
Schultz
Christian
C
Rozman
Jan
J
Hoeller
Daniela
D
Qiu
Chun-Hong
CH
Londoño
Marina B
MB
Ikezawa
Jun
J
Jedlicka
Peter
P
Stein
Birgit
B
Schwarzacher
Stephan W
SW
Wolfer
David P
DP
Ehrhardt
Nicole
N
Heuchel
Rainer
R
Nezis
Ioannis
I
Brech
Andreas
A
Schmidt
Mirko H H
MHH
Fuchs
Helmut
H
Gailus-Durner
Valerie
V
Klingenspor
Martin
M
Bogler
Oliver
O
Wurst
Wolfgang
W
Deller
Thomas
T
de Angelis
Martin Hrabé
MH
Dikic
Ivan
I
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*
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