Thorough mechanistic analysis of sertraline uptake and ensuing effects on cell physiology and a nice follow-up to your previous paper on this. Two comments/questions (for now):

1) Obviously for these kinds of membrane physical effects, concentration is key. You mention in the introduction that these are pharmacologically relevant concentrations; can you evaluate that further? With hydrophobic substrates, I think it is hard to related solution concentrations (in the media I presume) to cellular concentrations; not exactly a clear relationship. I guess the ideal sort of data that would be useful would by the sertraline/lipid ratio in these cells vs. the same ratio in neurons in a treated animal model. I guess that would help define the big, obvious follow up questions to this work, which is to what extent are these effects relevant to clinical sertraline use.

2) The comment you made about membrane fluidity and the temperature dependence on uptake is interesting (and commented on below). I want to point out that cells generally maintain a homeostatic membrane fluidity in response to changes to temperature (an old concept in the literature, often referred as a homoviscous effect) by changing lipid composition (e.g. increasing phospholipid unsaturation in cold temperatures). Also, outside of any fluidity effects, lower temperatures would be expected to reduce uptake via variety of mechanisms (lower sertraline solubility, lower permeability/flip flop rates, slower diffusion in general), independent of any changes to membrane structure.