- Messages
- 121
- Likes
- 422
You know that I adressed this in the first part of my ponderings, right? I literally referenced the same two studies. I said:
I consider the results of Qiu and Ma preliminary, because they are not on natural human cells. Qiu uses Xenopus, while Ma artificially transfects Panx1 into cells that do not have them normally. The research that shows ATP causing activation and opening of Panx1 is much higher quality, and larger. For me those two studies are indications that maybe sometimes eATP can close Panx1 channels, and we don't know what are the factors which decide if it opens or closes them.
Now, you propose, that we do know what the factor is, that it is solely the concentration. And you quote this as a source:
The problem here is that this sentence, in the original review that you linked, does not have a citation. It is nothing more than author's speculation. It's a very intetesting speculation, but a speculation nontheless. The Qiu and Ma studies do not prove this, because they induce Panx1 activation via electrical stimulation, not by administering low concentrations of eATP.
What would actually prove this is the case, is if someone took the same human cell type that was used in previous studies to show that eATP opens Panx1, like macrophages or astrocytes, and demonstrated that when you apply higher amounts of eATP, the Panx1 channels close. If it was done on macrophages, they would also need to apply the appropriate cytokines to ensure the macrophage stays in the M1 polarization, because a shift to M2 can occur spontaneously, and it changes how they respond to eATP.
So if you find a study like that, I will immediately admit that you're right on this, and I was wrong. But for now I'm gonna say this again - We. Do. Not. Know. why sometimes eATP makes Panx1 close. We do not even know if such an effect occurs in actual, natural human cells. The action of Panx1 in humans might be dependent on dozens of factors that we don not yet understand, and which Qiu and Ma failed to reproduce in their studies.
Ah, yes. My bad. I missed it. Yes, it would seem that you're right here, at least in your math. But since this directly contradicts what Naviaux has said in his presentation, I think it's time we ask him directly about it, so I've sent an email to him. I'll let you know once he responds.
The one possibility I see, for you to be wrong on your conclusion, is that the initial concentration is 100uM, and only falls to 12uM after 2 days. It might be that it is the initial concentration that breaks the eATP release feedback loop, and the upregulation of P2X7 isnt enough to undo it later when the concentration falls. But we'll see what Naviaux says.
I get that, but what you're effectively suggesting here is that the mechanism of ME/CFS involves an underactivation of P2X7, Panx1, and ATP being released to a lesser degree than in healthy people. This is not only directly opposite to what Naviaux said about ME/CFS, it is also not consistent with symptoms, and many research findings. My "ponderings" thread is basically two long essays explaining in detail, how OVERactivation of Panx1, P2X7 and INCREASED release of eATP is consistent with pretty much all the symptoms, as well as many of the key research findings. So this is why I'm extremaly skeptical of this hypothesis of yours - there is a mountain of arguments on the opposite side. I can't say for sure that you're wrong, but as it currently stands, your version seems incredibly unlikely to me.
See, but in the same study, they say clemastine potentiates the formation of large pores, as assesed by large molecule dye uptake. So it means that clemastine does potentiate eATP release from cells. Now, they say Panx1 is not involved here, because the potentiation of dye uptake did not change when they added carbenoxolone, which is a Panx1 inhibitor. Further, they state that carbenoxolone by itself caused dye uptake! This is the reverse of a multitude of other studies, which show carbenoxolone decreasing dye uptake. Something very weird is going on here. Now, it's interesting to note that in this study they used HEK cells, the same as the Ma et all study we mentioned earlier. To me, this is a suggestion that HEK cells are not representative of how P2X7 and Panx1 behave in natural human cells.
I consider the results of Qiu and Ma preliminary, because they are not on natural human cells. Qiu uses Xenopus, while Ma artificially transfects Panx1 into cells that do not have them normally. The research that shows ATP causing activation and opening of Panx1 is much higher quality, and larger. For me those two studies are indications that maybe sometimes eATP can close Panx1 channels, and we don't know what are the factors which decide if it opens or closes them.
Now, you propose, that we do know what the factor is, that it is solely the concentration. And you quote this as a source:
The problem here is that this sentence, in the original review that you linked, does not have a citation. It is nothing more than author's speculation. It's a very intetesting speculation, but a speculation nontheless. The Qiu and Ma studies do not prove this, because they induce Panx1 activation via electrical stimulation, not by administering low concentrations of eATP.
What would actually prove this is the case, is if someone took the same human cell type that was used in previous studies to show that eATP opens Panx1, like macrophages or astrocytes, and demonstrated that when you apply higher amounts of eATP, the Panx1 channels close. If it was done on macrophages, they would also need to apply the appropriate cytokines to ensure the macrophage stays in the M1 polarization, because a shift to M2 can occur spontaneously, and it changes how they respond to eATP.
So if you find a study like that, I will immediately admit that you're right on this, and I was wrong. But for now I'm gonna say this again - We. Do. Not. Know. why sometimes eATP makes Panx1 close. We do not even know if such an effect occurs in actual, natural human cells. The action of Panx1 in humans might be dependent on dozens of factors that we don not yet understand, and which Qiu and Ma failed to reproduce in their studies.
Ah, yes. My bad. I missed it. Yes, it would seem that you're right here, at least in your math. But since this directly contradicts what Naviaux has said in his presentation, I think it's time we ask him directly about it, so I've sent an email to him. I'll let you know once he responds.
The one possibility I see, for you to be wrong on your conclusion, is that the initial concentration is 100uM, and only falls to 12uM after 2 days. It might be that it is the initial concentration that breaks the eATP release feedback loop, and the upregulation of P2X7 isnt enough to undo it later when the concentration falls. But we'll see what Naviaux says.
I get that, but what you're effectively suggesting here is that the mechanism of ME/CFS involves an underactivation of P2X7, Panx1, and ATP being released to a lesser degree than in healthy people. This is not only directly opposite to what Naviaux said about ME/CFS, it is also not consistent with symptoms, and many research findings. My "ponderings" thread is basically two long essays explaining in detail, how OVERactivation of Panx1, P2X7 and INCREASED release of eATP is consistent with pretty much all the symptoms, as well as many of the key research findings. So this is why I'm extremaly skeptical of this hypothesis of yours - there is a mountain of arguments on the opposite side. I can't say for sure that you're wrong, but as it currently stands, your version seems incredibly unlikely to me.
See, but in the same study, they say clemastine potentiates the formation of large pores, as assesed by large molecule dye uptake. So it means that clemastine does potentiate eATP release from cells. Now, they say Panx1 is not involved here, because the potentiation of dye uptake did not change when they added carbenoxolone, which is a Panx1 inhibitor. Further, they state that carbenoxolone by itself caused dye uptake! This is the reverse of a multitude of other studies, which show carbenoxolone decreasing dye uptake. Something very weird is going on here. Now, it's interesting to note that in this study they used HEK cells, the same as the Ma et all study we mentioned earlier. To me, this is a suggestion that HEK cells are not representative of how P2X7 and Panx1 behave in natural human cells.
Last edited:
