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Abstract
Schizophrenia is a severe and chronic mental illness and affects a large portion of the world population. Clozapine is currently used in the treatment of schizophrenia patients, but it causes serious side effects, such as extrapyramidal symptoms (EPS). Thus, understanding the details of signaling pathways in pathology of schizophrenia is critical for the identification of novel therapeutic targets to develop more effective and specific antipsychotic drugs with fewer side effects. Glycogen synthase kinase (GSK)-3 is a protein kinase that has been shown to involve in schizophrenia, and clozapine has been reported to increase phosphorylation of glycogen synthase kinase (GSK)-3α/β (Ser21/9) in brain regions of rats related to schizophrenia. However, the pathways that mediate the effect of clozapine on GSK-3 were not clearly discovered. GABAB receptor has been reported to be associated with schizophrenia and activation of GABAB receptors may exert antipsychotic effects. Meanwhile, accumulated evidence suggests that the antipsychotic effect of clozapine may be partly mediated by modulating GABAB receptors. In addition, in our previous study, we have reported that GABAB receptors modulate GSK-3 signaling via the β-arrestin-dependent pathway. Activation of GABAB receptors will increase the phosphorylation of GSK-3α/β (Ser21/9) via activation of Akt and this effect depends on the existence of β-arrestin. These data indicate that clozapine may modulate GSK-3 activity via GABAB receptors. Here we report that clozapine increases phosphorylation of GSK-3α/β (Ser21/9) partly via GABAB receptors, which provides more specific target for treatment of schizophrenia, and avoidance of side effects of current antipsychotic drugs.
Highlights
Schizophrenia, characterized by episodes of psychotic symptoms, is a severe and chronic mental illness affecting 0.51% of the world population, and it has been the 5th leading cause of disability in industrialized countries
Densitomeric analysis of phosphorylation of Glycogen synthase kinase (GSK)-3α/β (Ser 21/9) in HEK293 cells transfected with GABAB receptors following treatment of clozapine
GABAB receptor antagonist, CGP52432 (10 μM, 30 min) pretreatment in HEK293 cells transfected with GABAB receptors blocked clozapine-induced increased level of phosphorylation of GSK-3α/β (Ser 21/9), as compared to those in control group
Summary
Schizophrenia, characterized by episodes of psychotic symptoms, is a severe and chronic mental illness affecting 0.51% of the world population, and it has been the 5th leading cause of disability in industrialized countries. Clozapine is currently used in treatment of schizophrenia patients; it causes serious side effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sexual dysfunctions, weight gain, and diabetes. Glycogen synthase kinase (GSK)-3 is a protein kinase that has been shown to involve in schizophrenia, and decreased phosphorylation of GSK-3α/β has been observed in post-mortem brain tissue of schizophrenia patients as well as animal models of schizophrenia [1,2,3]. Inhibition of GSK-3 decreases hyperlocomotor activity in animal models of schizophrenia [4]. A currently used antipsychotic drug for the treatment of schizophrenia, has been reported to increase phosphorylation of glycogen synthase kinase (GSK)-3α/β (Ser21/9) in brain regions of rats related to schizophrenia, such as the prefrontal cortex (PFC) and striatum, after repeated administration [5,6]. The pathways that mediate the effect of clozapine on GSK-3 were not clearly discovered
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