Direct visualization of phase separation induced by phenothiazine-type antipsychotic drugs in model lipid membranes

Abstract

Lipid rafts constitute dynamic assemblies within a bilayer, engaged in, e.g., signal transduction, membrane trafficking and cell polarization. Despite wide interest in the process of domain formation in binary or ternary lipid model systems, only a limited number of papers are devoted to the influence of different additives on this process. In particular, works devoted to the role of drugs in raft formation are missing. In the present study, the influence of trifluoperazine, thioridazine and chlorpromazine on domain organization in raft-mimicking model membranes was investigated. Using giant unilamellar vesicles formed from an equimolar DOPC:sphingomyelin:cholesterol mixture, we found that phenothiazines elevated the number of domains, decreased their area and markedly increased the total length of the domain border. The impact of studied drugs on phase separation in the raft lipid mixture was also confirmed by Laurdan generalized polarization measurements. Alteration of domain organization induced by antipsychotic drugs was very likely to arise from selective accumulation of phenothiazines in interfacial regions between liquid ordered and liquid disordered domains. Interpretation of the results allowed us to demonstrate new aspects underlaying mechanisms of action of phenothiazine-type antipsychotic drugs. To the best of our knowledge, this is the first report demonstrating the influence of drugs on domain morphology directly visualized in giant unilamellar vesicles.

Keywords::

• Giant unilamellar vesicles
• phenothiazine drugs
• lipid rafts

Declaration of interest: This work was supported by the Polish Committee for Scientific Research, funds for the Wrocław Medical University (Department of Biophysics). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.