Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics.

Sung Jin Park,Keisuke Kuroda,Young-Un Park,Kozo Kaibuchi,Kyung-Sun Park,Minh Dang Nguyen,Jaehoon Jeong,Sang Ki Park,Namgyu Lee,Haeryun Lee,Sung-Mo Kim

doi:10.1038/srep08694

Abstract

Disrupted-in-schizophrenia-1 (DISC1) has emerged as a convincing susceptibility gene for multiple mental disorders, but its mechanistic link to the pathogenesis of schizophrenia related psychiatric conditions is yet to be further understood. Here, we showed that DISC1 localizes to the outer surface of the endoplasmic reticulum (ER). EXOC1, a subunit of the exocyst complex, interacted with DISC1 and affected its recruitment to inositol-1,4,5-trisphosphate receptor 1 (IP3R1). Notably, knockdown of DISC1 and EXOC1 elicited an exaggerated ER calcium response upon stimulation of IP3R agonists. Similar abnormal ER calcium responses were observed in hippocampal neurons from DISC1-deficient mutant mice. Moreover, perturbation of ER calcium dynamics upon DISC1 knockdown was effectively reversed by treatment with antipsychotic drugs, such as clozapine and haloperidol. These results collectively indicate that DISC1 is a regulatory factor in ER calcium dynamics, linking a perturbed intracellular calcium signaling and schizophrenia pathogenesis.

Highlights

Disrupted-in-schizophrenia-1 (DISC1) has emerged as a convincing susceptibility gene for multiple mental disorders, but its mechanistic link to the pathogenesis of schizophrenia related psychiatric conditions is yet to be further understood
In this study, we propose that DISC1 has a novel intracellular function linked to regulation of the endoplasmic reticulum (ER) calcium dynamics via IP3Rs
The domain of DISC1 responsible for localization to the ER is critical for IP3R1 interaction; this indicates that IP3R1 is the destination for DISC1 on ER

Summary

Introduction

Disrupted-in-schizophrenia-1 (DISC1) has emerged as a convincing susceptibility gene for multiple mental disorders, but its mechanistic link to the pathogenesis of schizophrenia related psychiatric conditions is yet to be further understood. Perturbation of ER calcium dynamics upon DISC1 knockdown was effectively reversed by treatment with antipsychotic drugs, such as clozapine and haloperidol These results collectively indicate that DISC1 is a regulatory factor in ER calcium dynamics, linking a perturbed intracellular calcium signaling and schizophrenia pathogenesis. Possible association between ER and EXOC1, a component of the exocyst complex, was initially suggested based on the finding that EXOC1 regulates cortical ER inheritance and accumulation of Sec61p, a core complex involved in protein translocation across the ER membrane[20] This hypothesis was supported by independent studies showing physical and functional interactions of subunits of the exocyst complex with the Sec61p complex[21,22] and IP3Rs23

Methods

Results

Conclusion