Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics.
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.
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Sung Jin
SJ
Park
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Jaehoon
J
Jeong
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Young-Un
YU
Park
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, 790-784, Republic of Korea.
Kyung-Sun
KS
Park
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, 790-784, Republic of Korea.
Haeryun
H
Lee
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Namgyu
N
Lee
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Sung-Mo
SM
Kim
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Keisuke
K
Kuroda
Hotchkiss Brain Institute, Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1.
Minh Dang
MD
Nguyen
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Kozo
K
Kaibuchi
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Sang Ki
SK
Park
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000378:metabolism
D014150:Antipsychotic Agents; C498794:Disc1 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D033921:Vesicular Transport Proteins; D002118:Calcium