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Some layman's questions about your article

Posted by ArniePerlstein on 19 Apr 2012 at 18:48 GMT

Not being a biologist, I went straight to your Discussion section where I would have the best chance of understanding the text, which would be the gist of the significance of your paper.

Here are some quick questions, which I hope will have quick answers:

You wrote: "We presented evidence that supports an evolutionarily informed, cell biological explanatory model of cellular membrane accumulation by sertraline in a simple eukaryote with an intact secretory pathway."

Q1: How could it be other than "cell biological"?

Q2: What is an "intact secretory pathway"?

You wrote: ""Explication of our model begins with the passive internalization of neutral sertraline molecules at the plasma membrane. "

Q3: What other membranes are there?

You wrote: "However, passively internalized sertraline appears to be a potent substrate for ATP-dependent efflux pumps."

Q4: "substrate" means something that the pumps pump?

You wrote: "In fact, efflux may explain the paradoxical observation that at physiological pH, sertraline is predicted to be over 99% ionized yet only a minority fraction (10–15%) is observed to be soluble at equilibrium. Our interpretation is that the ionized pool of sertraline is actively depleted both by ATP-dependent efflux /and/ by sequestration in cellular membranes as a neutral species."

Q5: What significance of sertraline being almost entirely ionized? Does ionization ordinarily lead to solubility?

And finally, as to the final two paragraphs of your Discussion section:

Q6: Can you give the gist of the last 2 paragraphs in layman's English?


No competing interests declared.

RE: Some layman's questions about your article

eperlste replied to ArniePerlstein on 21 Apr 2012 at 20:54 GMT

A1: As opposed to biochemical, which is often the case for drugs that were "reverse engineered." Reverse engineered means Pharma/biotech/academic lab started with a single drug target molecule, usually a protein, that was compellingly associated with a disease; then they isolated potent chemical matter (i.e., clinical drugs) that modulated the function of said protein; finally, they figured out how to dose it safely in human patients. Problem is many clinical drugs fail during trials because they are ineffective, exposing a fatal flaw in the original oversimplification of going all in on one drug target for a complex disease.

A2: Normal eukaryotic cells have intact secretory pathways that allow them to manufacture cellular material and then transport these products from one internal location to another, or from inside the cell to outside the cell, the process called secretion. By contrast, the red blood cell is a highly specialized cell type - basically a giant sac of hemoglobin and cytoskeletal matrix. In the process of becoming this sac, the internal compartments, or organelles, were lost.

A3: Internal/intracellular membranes. Everyone forgets that our cells are like Babushka dolls, with smaller sealed compartments inside the outermost "skin" of the cell, which is a membrane, too. Also, don't forget that membranes are bilayers! (Please see this excellent Wikipedia summary for what I mean by a bilayer:

A4: Yes.

A5: Ionization leads to high solubility in the water or aqueous phase, i.e., not IN membranes. Think of a vinaigrette. Ionized molecules of sertraline have a net charge, in this case positive (i.e., an extra proton), and so will reside in the vinegar phase. On the other hand, the unionized form of sertraline/Zoloft is uncharged, and, because it is sufficiently hydrophobic, will reside in the oil phase.

A6: The neurotrophic/neurogenic hypothesis may be more grounded in membrane biology than we currently appreciate.

No competing interests declared.