Neural cell adhesion molecule modulates dopaminergic signaling and behavior by regulating dopamine D2 receptor internalization.
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Neural cell adhesion molecule modulates dopaminergic signaling and behavior by regulating dopamine D2 receptor internalization. / Xiao, Meifang; Xu, Jinchong; Tereshchenko, Yuliya; Novak, Daniel; Schachner, Melitta; Kleene, Ralf.
in: J NEUROSCI, Jahrgang 29, Nr. 47, 47, 2009, S. 14752-14763.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Neural cell adhesion molecule modulates dopaminergic signaling and behavior by regulating dopamine D2 receptor internalization.
AU - Xiao, Meifang
AU - Xu, Jinchong
AU - Tereshchenko, Yuliya
AU - Novak, Daniel
AU - Schachner, Melitta
AU - Kleene, Ralf
PY - 2009
Y1 - 2009
N2 - The dopaminergic system plays an important role in the etiology of schizophrenia, and most antipsychotic drugs exert their functions by blocking dopamine D(2) receptors (D(2)Rs). Since the signaling strength mediated by D(2)Rs is regulated by internalization and degradation processes, it is crucial to identify molecules that modulate D(2)R localization at the cell surface. Here, we show that the neural cell adhesion molecule (NCAM) promotes D(2)R internalization/desensitization and subsequent degradation via direct interaction with a short peptide in the third intracellular loop of the D(2)R. NCAM deficiency in mice leads to increased numbers of D(2)Rs at the cell surface and augmented D(2)R signaling as a result of impaired D(2)R internalization. Furthermore, NCAM-deficient mice show higher sensitivity to the psychostimulant apomorphine and exaggerated activity of dopamine-related locomotor behavior. These results demonstrate that, in addition to its classical function in cell adhesion, NCAM is involved in regulating the trafficking of the neurotransmitter receptor D(2)R as well as receptor-mediated signaling and behavior, thus implicating NCAM as modulator of the dopaminergic system and a potential pharmacological target for dopamine-related neurological and psychiatric disorders.
AB - The dopaminergic system plays an important role in the etiology of schizophrenia, and most antipsychotic drugs exert their functions by blocking dopamine D(2) receptors (D(2)Rs). Since the signaling strength mediated by D(2)Rs is regulated by internalization and degradation processes, it is crucial to identify molecules that modulate D(2)R localization at the cell surface. Here, we show that the neural cell adhesion molecule (NCAM) promotes D(2)R internalization/desensitization and subsequent degradation via direct interaction with a short peptide in the third intracellular loop of the D(2)R. NCAM deficiency in mice leads to increased numbers of D(2)Rs at the cell surface and augmented D(2)R signaling as a result of impaired D(2)R internalization. Furthermore, NCAM-deficient mice show higher sensitivity to the psychostimulant apomorphine and exaggerated activity of dopamine-related locomotor behavior. These results demonstrate that, in addition to its classical function in cell adhesion, NCAM is involved in regulating the trafficking of the neurotransmitter receptor D(2)R as well as receptor-mediated signaling and behavior, thus implicating NCAM as modulator of the dopaminergic system and a potential pharmacological target for dopamine-related neurological and psychiatric disorders.
M3 - SCORING: Zeitschriftenaufsatz
VL - 29
SP - 14752
EP - 14763
JO - J NEUROSCI
JF - J NEUROSCI
SN - 0270-6474
IS - 47
M1 - 47
ER -
