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Nice paper

Posted by itaybudin on 21 May 2012 at 21:29 GMT

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.

No competing interests declared.

RE: Nice paper

eperlste replied to itaybudin on 22 May 2012 at 14:43 GMT

Thanks for the post, Itay! Please see my replies below:

A1: Yes, concentration is King. We have already performed cellular uptake experiments with tritiated sertraline on PC12 cells (rat neuronal cell line), and are about to embark on subcellular fractionation experiments in these cells, analogously to what we did with yeast in this paper. I agree that doing animal work would be ideal, but my lab is not set up to do those experiments. I have spoken to Randy Blakely about this question, and his lab's SERT mutant mouse would be the perfect specimen to examine in situ membrane partitioning. Sounds like a job for

A2: I concede that the low-temperature experiment is only suggestive in re membrane fluidity. The reviewers hammered us on this point, to their credit. We thought about doing non-temperature perturbation experiments directed at manipulating ergosterol levels, but never got around to it. What would you suggest as the cleanest way to address the role of membrane fluidity on sertraline uptake/accumulation in yeast cells?

No competing interests declared.