Comments on: Feeling a little chilli… - Updated http://badchemist.net/good-science/feeling-a-little-chilli Science, Pseudoscience and Junk Thu, 28 Aug 2008 20:34:53 +0000 http://wordpress.org/?v=2.5 By: Dr Aust http://badchemist.net/good-science/feeling-a-little-chilli#comment-13 Dr Aust Thu, 11 Oct 2007 16:18:58 +0000 http://badchemist.net/?p=9#comment-13 Speaking as a bioscientist who works a bit on ion channels and has even dabbled in this specific area, it is a surprise that QX314 would pass through the ion channel pore into the cell. These channels are what we call "cation non-selective", but that typically means they let through alkali and alkaline earth metal cations - Na+, K+, Ca2+. QX314 is a substantially bigger molecule - it is lidocaine with an extra ethyl group on the terminal substituted nitrogen, so that it is now a quaternary amine and therefore has to be a cation. Thus one might expect it to be "size excluded" from going through unless the channel pore is quite "big" in molecular terms. This is something that has not previously been reported for this class of channels, although there are some vague precedents for other types. BTW, as you probably know most local anaesthetics are ionizable weak bases - like QX314's "parent" lidocaine which is a tertiary amine - and get into cells by diffusion across the membrane in the <i>uncharged</i> form, following which they ionize and block the channel from the inside as the charged species). I suppose the implication is that the QX314 molecule is adopting a sort of linear-ish form and "wiggling" its way through the open channel. Anyway, a very interesting paper, but I wil be watching to see how quickly it gets confirmed by other labs. Speaking as a bioscientist who works a bit on ion channels and has even dabbled in this specific area, it is a surprise that QX314 would pass through the ion channel pore into the cell. These channels are what we call “cation non-selective”, but that typically means they let through alkali and alkaline earth metal cations - Na+, K+, Ca2+. QX314 is a substantially bigger molecule - it is lidocaine with an extra ethyl group on the terminal substituted nitrogen, so that it is now a quaternary amine and therefore has to be a cation. Thus one might expect it to be “size excluded” from going through unless the channel pore is quite “big” in molecular terms. This is something that has not previously been reported for this class of channels, although there are some vague precedents for other types.

BTW, as you probably know most local anaesthetics are ionizable weak bases - like QX314’s “parent” lidocaine which is a tertiary amine - and get into cells by diffusion across the membrane in the uncharged form, following which they ionize and block the channel from the inside as the charged species).

I suppose the implication is that the QX314 molecule is adopting a sort of linear-ish form and “wiggling” its way through the open channel. Anyway, a very interesting paper, but I wil be watching to see how quickly it gets confirmed by other labs.

]]> By: PJ http://badchemist.net/good-science/feeling-a-little-chilli#comment-4 PJ Thu, 04 Oct 2007 11:30:47 +0000 http://badchemist.net/?p=9#comment-4 Interesting, a better description of the study is <a href="http://www.sciam.com/article.cfm?articleID=674E972E-E7F2-99DF-39A3406D0D2B2A7C&chanID=sa003 rel="nofollow">here</a> but I can't find it in Nature yet. I hope they properly differentiated the irritant and (alleged) counterirritant properties of capsaicin by using a capsaicin only control (can't tell from that article) since you might expect that injecting capsaicin around a nerve (!) might produce such a burning that heat perception was disrupted. You'd have thought a different vanilloid ligand might be a better approach, maybe a salicylate. <em>Edited by badchemist to make link shorter.</em> Interesting, a better description of the study is here

but I can’t find it in Nature yet.

I hope they properly differentiated the irritant and (alleged) counterirritant properties of capsaicin by using a capsaicin only control (can’t tell from that article) since you might expect that injecting capsaicin around a nerve (!) might produce such a burning that heat perception was disrupted.

You’d have thought a different vanilloid ligand might be a better approach, maybe a salicylate.

Edited by badchemist to make link shorter.

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