Park Sung Jin, Jeong Jaehoon, Park Young-Un, Park Kyung-Sun, Lee Haeryun, Lee Namgyu, Kim Sung-Mo, Kuroda Keisuke, Nguyen Minh Dang, Kaibuchi Kozo, Park Sang Ki
Department of Life Sciences, Pohang University of Science and Technology, 790-784, Republic of Korea.
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, 790-784, Republic of Korea.
Sci Rep. 2015 Mar 3;5:8694. doi: 10.1038/srep08694.
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.
精神分裂症相关基因1（DISC1）已成为多种精神障碍令人信服的易感基因，但其与精神分裂症相关精神疾病发病机制的机制联系尚待进一步了解。在此，我们表明DISC1定位于内质网（ER）的外表面。外泌体复合物的一个亚基EXOC1与DISC1相互作用，并影响其向内质网肌醇-1,4,5-三磷酸受体1（IP3R1）的募集。值得注意的是，敲低DISC1和EXOC1会在刺激IP3R激动剂时引发夸张的内质网钙反应。在DISC1缺陷型突变小鼠的海马神经元中也观察到类似的内质网钙反应异常。此外，用抗精神病药物如氯氮平和氟哌啶醇治疗可有效逆转敲低DISC1后内质网钙动力学的扰动。这些结果共同表明，DISC1是内质网钙动力学的调节因子，将细胞内钙信号紊乱与精神分裂症发病机制联系起来。
