Proteome Analysis of PC12 Cells Reveals Alterations in Translation Regulation and Actin Signaling Induced by Clozapine

Urszula Jankowska,Bozena Skupien-Rabian,Bianka Swiderska,Gabriela Prus,Sylwia Kedracka-Krok,Marta Dziedzicka-Wasylewska

doi:10.1007/s11064-021-03348-4

Abstract

Although antipsychotics are routinely used in the treatment of schizophrenia for the last decades, their precise mechanism of action is still unclear. In this study, we investigated changes in the PC12 cells’ proteome under the influence of clozapine, risperidone, and haloperidol to identify protein pathways regulated by antipsychotics. Analysis of the protein profiles in two time points: after 12 and 24 h of incubation with drugs revealed significant alterations in 510 proteins. Further canonical pathway analysis revealed an inhibition of ciliary trophic factor signaling after treatment with haloperidol and showed a decrease in acute phase response signaling in the risperidone group. Interestingly, all tested drugs have caused changes in PC12 proteome which correspond to inhibition of cytokines: tumor necrosis factor (TNF) and transforming growth factor beta 1 (TGF-β1). We also found that the 12-h incubation with clozapine caused up-regulation of protein kinase A signaling and translation machinery. After 24 h of treatment with clozapine, the inhibition of the actin cytoskeleton signaling and Rho proteins signaling was revealed. The obtained results suggest that the mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) play a central role in the signal transduction of clozapine.

Highlights

Antipsychotics are commonly used for treating schizophrenia, bipolar disorder, and other psychotic diseases [2]
We aimed to explore alterations in the protein profile of PC12 cells after incubation with antipsychotic drugs: clozapine, risperidone, and haloperidol for 12 and 24 h
As alterations in protein profile revealed in our study have often not been linked to antipsychotics before, we discuss it in the context of schizophrenia

Summary

Introduction

Antipsychotics are commonly used for treating schizophrenia, bipolar disorder, and other psychotic diseases [2]. Treatment of schizophrenia is considered one of the greatest challenges of modern clinical psychiatry, as around 30% of. Different therapeutic effects of drugs are probably related to their diverse affinity for individual receptors, but another explanation is based on the observation that the conformational changes of the receptor may be different depending on the ligand, leading to the activation of different signal transduction cascades [4]. All antipsychotics block the dopamine D2 receptor and increase the pathway of cyclic AMP/protein kinase A (PKA) [2]. The pathways interplay at various levels of signal transduction, i.e., secondary messengers, signaling proteins/kinases/phosphatases, and transcription factors, which generates a complex system of mutual dependencies [5]

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