Thiazolidinediones Alter Lipid Bilayer Properties and Native Voltage-Gated Sodium Channel Function

Abstract

Thiazolidinediones (TZD) are selective peroxizome-proliferator receptor gamma (PPARγ) agonists that are used to treat hyperglycemia in type 2 diabetes. In addition to their hypoglycemic actions they have anti-inflammatory, anti-atherosclerotic and cardiovascular effects, but PPARγ activation does not account for all their actions. Three TZDs - troglitazone (Resulin), rosiglitazone (Avandia), and pioglitazone (Actos) - have been marketed; troglitazone was subsequently withdrawn due to hepatotoxicity and a precursor TZD - ciglitazone- was discontinued after phase II trials. TZDs, with troglitazone being the most potent, modulate L-type calcium and delayed-rectifier potassium channels by a seemingly PPARγ-independent mechanism. This could result from the adsorption of the amphiphilic TZDs to the membrane/solution interface, which can alter bilayer properties such as thickness, intrinsic curvature and the elastic moduli, and thus membrane protein function. We therefore examined whether TZDs alter lipid bilayer properties. We exploited the sensitivity of gramicidin channels to changes in bilayer properties to test for TZD-induced bilayer effects. TZDs alter gramicidin channel function and shift the monomer-dimer equilibrium toward the conducting dimers. Using gramicidin channels of different lengths we find that the TZD effects do not vary with changes in hydrophobic mismatch. Increasing bilayer stiffness with cholesterol amplifies the TZD-mediated changes in gramicidin channel function. Based on the concentrations at which we observe changes in gramicidin lifetime and appearance frequency, the potency is troglitazone>rosiglitazone>ciglitazone>pioglitazone, consistent with their effects on native membrane proteins. We examined the TZDs effects in native membranes using neuronal voltage-gated sodium channels (NaV) using whole-cell recordings. All TZDs caused a negative shift in the voltage-dependence of inactivation at concentrations similar to those that alter gramicidin channel function. Our results show that TZDs affect bulk membrane properties at concentrations that modulate native ion channels.