Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Jun;16(6):635-54.
doi: 10.1111/tra.12272. Epub 2015 Apr 9.

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

James A Daniel  1   2 , Ngoc Chau  1 , Mohammed K Abdel-Hamid  3 , Lingbo Hu  4 , Lisa von Kleist  5 , Ainslie Whiting  1 , Sai Krishnan  1 , Peter Maamary  1 , Shannon R Joseph  4 , Fiona Simpson  4 , Volker Haucke  5 , Adam McCluskey  3 , Phillip J Robinson  1
Affiliations
Free article

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

James A Daniel et al. Traffic. 2015 Jun.
Free article

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.

Keywords: antipsychotic drugs; calmidazolium; chlorpromazine; drug discovery; dynamin; flunarizine; fluphenazine; phenothiazines; small molecule inhibitors; stemetil; trifluoperazine.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

LinkOut - more resources