Phenothiazine-derived antipsychotic drugs inhibit dynamin and vlathrin-mediated endocytosis

Daniel, James A., Chau, Ngoc, Abdel-Hamid, Mohammed K., Hu, Lingbo, von Kleist, Lisa, Whiting, Ainslie, Krishnan, Sai, Maamary, Peter, Joseph, Shannon R., Simpson, Fiona, Haucke, Volker, McCluskey, Adam and Robinson, Philip J. (2015) Phenothiazine-derived antipsychotic drugs inhibit dynamin and vlathrin-mediated endocytosis. Traffic, 16 6: 635-654. doi:10.1111/tra.12272


Author Daniel, James A.
Chau, Ngoc
Abdel-Hamid, Mohammed K.
Hu, Lingbo
von Kleist, Lisa
Whiting, Ainslie
Krishnan, Sai
Maamary, Peter
Joseph, Shannon R.
Simpson, Fiona
Haucke, Volker
McCluskey, Adam
Robinson, Philip J.
Title Phenothiazine-derived antipsychotic drugs inhibit dynamin and vlathrin-mediated endocytosis
Journal name Traffic   Check publisher's open access policy
ISSN 1600-0854
1398-9219
Publication date 2015-06-01
Year available 2015
Sub-type Article (original research)
DOI 10.1111/tra.12272
Open Access Status
Volume 16
Issue 6
Start page 635
End page 654
Total pages 20
Place of publication Malden, MA United States
Publisher Wiley-Blackwell Publishing
Collection year 2016
Language eng
Formatted abstract
Chlorpromazine is a phenothiazine-derived antipsychotic drug (APD) that inhibits clathrin-mediated endocytosis (CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I (dynI) in the 2–12 µm range, the most potent being trifluoperazine (IC50 2.6 ± 0.7 µm). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure–activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.
Keyword Antipsychotic drugs
Calmidazolium
Chlorpromazine
Drug discovery
Dynamin
Flunarizine
Fluphenazine
Phenothiazines
Small molecule inhibitors
Stemetil
Trifluoperazine
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
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