Tubulin/microtubules as novel clozapine targets

Mizuki Hino, Takeshi Kondo, Yasuto Kunii, Junya Matsumoto, Akira Wada, Shin ichi Niwa, Mitsutoshi Setou, Hirooki Yabe

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Aim: Clozapine is currently the only effective drug for treatment-resistant schizophrenia; nonetheless, its pharmacological mechanism remains unclear, and its administration is limited because of severe adverse effects. By comparing the binding proteins of clozapine and its derivative olanzapine, which is safer but less effective than clozapine, we attempted to clarify the mechanism of action specific to clozapine. Methods: First, using the polyproline rod conjugates attached with clozapine or olanzapine, clozapine-binding proteins in extracts from the cerebra of 7-week-old ICR mice were isolated and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify proteins. Second, the effect of clozapine on tubulin polymerization was determined turbidimetrically. Finally, the cellular effects of clozapine were observed in HeLa cells by immunofluorescence microscopy. Results: Alpha and β tubulins were the most abundant clozapine-binding proteins. We also found that clozapine directly binds with α and β tubulin heterodimers to inhibit their polymerization to form microtubules and disturbs the microtubule network, causing mitotic arrest in HeLa cells. Conclusion: These results suggest that α and β tubulin heterodimers are targeted by the clozapine and the microtubules are involved in the etiology of schizophrenia.

Original languageEnglish
Pages (from-to)32-41
Number of pages10
JournalNeuropsychopharmacology Reports
Issue number1
Publication statusPublished - 2022 Mar


  • clozapine
  • microtubule
  • olanzapine
  • schizophrenia
  • tubulin

ASJC Scopus subject areas

  • Clinical Psychology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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