Not really. I mean, there is some evidence that such a thing can maybe happen sometimes, but right now that evidence is very limited and of poor quality. I wrote about it in Part 1 of my ponderings.
So far we only know for sure that eATP opens Panx1, in most cases.
In your ponderings you're thinking about pannexin-1 (Panx1) in terms of its relationship with P2X7.
But it was discovered in 2008/2009 by at least two different groups (
Qiu et al and
Ma et al) that Panx1 actually has its own receptor for external ATP (eATP) that operates independently of P2X7. External ATP is able to inhibit Panx1 via this receptor.
This eATP receptor acts as negative feedback mechanism to help prevent too great an outflow of ATP from the cell due to activation of P2X7 (by eATP). As a
2013 review states:
At low ATP concentrations, the purinergic receptors [e.g., P2X7] activate Panx1 resulting in amplified ATP release. As the ATP concentration builds up in the vicinity or within the vestibulum of the Panx1 channel, the self inhibition will limit further ATP release.
The binding site on Panx1 for inhibition by eATP is very similar to the one on P2X7 for activation by eATP, and most of the same ligands/drugs that bind to P2X7 also bind to Panx1. Interestingly, when such a ligand binds to Panx1 it acts as an inhibitor of Panx1 regardless of whether it is an antagonist or agonist at P2X7. Additionally, the concentration of such a ligand required to inhibit Panx1 is greater than that to inhibit P2X7. (This includes, e.g., suramin.)
Note that Brilliant Blue FCF (BB FCF), which inhibits Panx1 but not P2X7, binds to a binding site that overlaps with the eATP binding site on Panx1 but is distinct.
So BB FCF acts on Panx1 in a very similar way to eATP. (
Reference)
I still think suramin probably directly closes Panx1, even at the dose used in the autism trial. Because that's what Naviaux said in his presentations. I'm happy to be proven wrong by
@nandixon or anyone else, but I need to see their math, with sources for all the important values. So far he hasn't produced those.
I gave the values/sources I'm using previously:
In the human pediatric trial
study, the amount of suramin administered resulted in a blood concentration of suramin of about 12 micromolar… I'd been thinking in terms of an IC50 [for suramin at P2X7] of about 70 micromolar per this
study.
Based on these numbers, one could say as a very crude estimate that suramin might be giving a 10% inhibition of P2X7 in Naviaux’ human trial, and this small amount would be offset by the increase in mRNA gene expression of P2X7 that is indicated to happen by Naviaux’ poly(IC) autism mouse model
study upon treatment with suramin, where a 60% reduction in P2X7 expression was mostly normalized.
Naviaux would say that this increase in P2X7 expression was due to a decrease in (an excess) of eATP, and that may be correct. But eATP can't be properly measured due to local concentration effects, as Naviaux points out in the mouse study, so we don't know.
So the idea with clemastine is just to try to capture what is outwardly an apparent net effect of an up-regulation at P2X7 and see what happens.
How a biochemical result is achieved can obviously be just as important as the result itself but note that clemastine effectively up-regulates P2X7 by making it more sensitive to eATP while apparently not affecting Panx1:
Considering these data together with the rapid reversibility of clemastine effects, we have not obtained evidence that clemastine-dependent augmentation of hP2X7 currents involves recruitment and/or opening of pannexin-like hemichannels. [
Reference]
(Clemastine is an allosteric modifier of P2X7 and doesn't actually bind to the eATP binding site which would trigger involvement of Panx1.)
