Propranolol induces large-scale remodeling of lipid bilayers: tubules, patches, and holes

Herein, we report fluorescence microscopy analysis of the interaction between propranolol (PPN), a beta-adrenergic blocking agent, and planar supported lipid bilayers (SLBs), as model membranes. The results indicate that PPN can remarkably promote largescale remodeling in SLBs with various lipid compositions. It was found that PPN insertion induces the formation of long microtubules that can retract into hemispherical caps on the surface of the bilayer. These transformations are dynamic, partially reversible, and dependent upon the drug concentration. Quantitative analysis revealed a three-step model for PPN–lipid bilayer interaction, with the first step involving interfacial electrostatic adsorption, the second step centered on hydrophobic insertion, and the third step associated with membrane disruption and hole formation. By introducing cholesterol, phosphoethanolamine, phosphatidylglycerol, and phosphatidylserine lipids into the phosphocholine SLBs, it was illustrated that both the chemistry of the lipid headgroups and the packing of lipid acyl chains can substantially affect the particular steps in the interactions between PPN and lipid bilayers. Our findings may help to elucidate the possible mechanisms of PPN interaction with lipid membranes, the toxic behavior and overdosage scenarios of beta-blockers, and provide valuable information for drug development and modification.