Accumulation of Sertraline leads to Autophagy in S. Cerevisiae

[sekio]

Here we take a novel, evolutionarily informed approach to studying the effects of the selective-serotonin reuptake inhibitor sertraline/Zoloft® on cell physiology in the model eukaryote Saccharomyces cerevisiae (budding yeast), which lacks a serotonin transporter entirely. [...] sertraline enters yeast cells and then reshapes vesiculogenic membranes by a complex process. Internalization of the neutral species proceeds by simple diffusion, is accelerated by proton motive forces generated by the vacuolar H+-ATPase, but is counteracted by energy-dependent xenobiotic efflux pumps. At equilibrium, a small fraction (10–15% ) of reprotonated sertraline is soluble while the bulk (90–85% ) partitions into organellar membranes by adsorption to interfacial anionic sites or by intercalation into the hydrophobic phase of the bilayer. Asymmetric accumulation of sertraline in vesiculogenic membranes leads to local membrane curvature stresses that trigger an adaptive autophagic response.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034024

The big question is what happens in mammalian cells at normal doses of such compounds. These may well not be enough to cause membrane trouble, but there's already evidence to the contrary. A second big question is: does this effect account for some of the actual neurological effects of these drugs? And a third one is, how many other compounds are doing something similar? The more you look, the more you find. . .

http://pipeline.corante.com/archives/2012/05/16/antidepressant_drugs_and_cell_membranes.php

Very interesting, to say the least.

 

[endotropic]

The fact that they report these findings at micromolar concentrations makes me think that lower concentrations aren't causing these autophagocytotic effects, and I think it's extremely unlikely that normal doses of Zoloft are reaching micromolar concentrations in the brain. Still, neurons are probably more sensitive than yeast, so I'd like to see what followups come from this. As far as this mechanism causing the neurological effects of these drugs, a commenter from the pipeline link said it perfectly:

"The other enantiomers of sertraline are apparently inactive, which suggests that the psychoactive effects of sertraline are not due to pysichochemical interactions with membranes. It's a pretty perfect control, IMHO."