Antidepressants are modifiers of lipid bilayer properties

Abstract

The two major classes of antidepressants, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), inhibit neurotransmitter reuptake at synapses. They also have off-target effects on proteins other than neurotransmitter transporters, which may contribute to both desired changes in brain function and the development of side effects. Many proteins modulated by antidepressants are bilayer spanning and coupled to the bilayer through hydrophobic interactions such that the conformational changes underlying their function will perturb the surrounding lipid bilayer, with an energetic cost (ΔGdef) that varies with changes in bilayer properties. Here, we test whether changes in ΔGdef caused by amphiphilic antidepressants partitioning into the bilayer are sufficient to alter membrane protein function. Using gramicidin A (gA) channels to probe whether TCAs and SSRIs alter the bilayer contribution to the free energy difference for the gramicidin monomer⇔dimer equilibrium (representing a well-defined conformational transition), we find that antidepressants alter gA channel activity with varying potency and no stereospecificity but with different effects on bilayer elasticity and intrinsic curvature. Measuring the antidepressant partition coefficients using isothermal titration calorimetry (ITC) or cLogP shows that the bilayer-modifying potency is predicted quite well by the ITC-determined partition coefficients, and channel activity is doubled at an antidepressant/lipid mole ratio of 0.02–0.07. These results suggest a mechanism by which antidepressants could alter the function of diverse membrane proteins by partitioning into cell membranes and thereby altering the bilayer contribution to the energetics of membrane protein conformational changes.

Direct Derivation of Free Energies of Membrane Deformation and Other Solvent Density Variations From Enhanced Sampling Molecular Dynamics

“…It is increasingly recognized that the biophysical properties of the membrane, whether in physiological or in vitro conditions, influence the structure and function of many membrane‐associated proteins . One reason is that the molecular mechanisms of membrane proteins often entail transient or persistent deformations in the surrounding membrane; thus, alteration of the elastic properties or natural curvature of these membranes, through variations in their lipid composition, is one way to regulate protein activity.…”

Receptor-independent membrane mediated pathways of serotonin action

“…Therefore, both the vesicular and the plasma membranes (near the release sites) are exposed to a considerable amount of serotonin. Small amphipathic molecules, for example, specific anesthetics, are known to alter the physical properties of the membrane, such as membrane fluidity [26][27][28][29][30] . If serotonin also does so, then that in turn can affect cellular functions, including membrane protein function, membrane affinity of other molecules as a prerequisite for subsequent receptor binding, and key cellular processes such as exocytosis and endocytosis.…”

Altered Membrane Mechanics Provides a Receptor‐Independent Pathway for Serotonin Action

“…[20] Small amphipathic molecules, for example,s pecific anesthetics, are knownt oa lter the physical properties of the membrane, such as membrane fluidity. [21][22][23][24][25] It has also been shown that isothermal compressibility of lipid monolayers can be alteredb ys mall serotonin-related molecules (such as melatonin) at % 1mm concentration, and even by serotonin at higher concentrations. [26] Furthermore, serotonin binding to raft-like mixed model membranes was shown to alter domain size.…”