GSK‐3β Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia

Summary Introduction Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechan...

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Published in:CNS neuroscience & therapeutics 2017-02, Vol.23 (2), p.174-187
Main Authors: Wang, Jing‐Ru, Sun, Pei‐Hua, Ren, Zhao‐Xiang, Meltzer, Herbert Y., Zhen, Xue‐Chu
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic - pharmacology
Animals
beta-Arrestins - metabolism
Cyclic AMP - metabolism
Desensitization
Disease Models, Animal
Dopamine Agonists - pharmacology
Dopamine D1 receptor
Endocytosis - drug effects
Endocytosis - genetics
Enzyme Inhibitors - pharmacology
Fenoldopam - pharmacology
Glycogen Synthase Kinase 3 beta - genetics
Glycogen Synthase Kinase 3 beta - metabolism
GSK‐3β
Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics
HEK293 Cells
Humans
Indoles - pharmacology
Internalization
Lithium Chloride - pharmacology
Maleimides - pharmacology
Original
Prefrontal Cortex - drug effects
Prefrontal Cortex - metabolism
Protein Transport - drug effects
Rats
Receptors, Dopamine D1 - metabolism
Schizophrenia
Schizophrenia - chemically induced
Schizophrenia - metabolism
Schizophrenia - pathology
β‐arrestin
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Summary:Summary Introduction Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function. Aims To investigate the physical interaction and functional modulation between D1R and GSK‐3β. Results D1R and GSK‐3β physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C‐terminus of D1R. Inhibition of GSK‐3β impaired D1R activation along with a decrease in D1R‐GSK‐3β interaction. GSK‐3β inhibition reduced agonist‐stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of β‐arrestin‐2. Similarly, inhibition of GSK‐3β in rat PFC also resulted in impaired D1R activation and association with GSK‐3β. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK‐3β activity and D1R‐GSK‐3β association and decreased D1R activation in the PFC. Conclusions The present work identified GSK‐3β as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK‐3β‐regulated D1R function which may underlie D1R dysfunction in schizophrenia.
ISSN:1755-5930
1755-5949
DOI:10.1111/cns.12664