Role of calcium channels

Inara

Inara

Senior Member (Voting Rights)
[I don't know whether this is the right subforum to post...if not may I kindly ask to move it? Moderator note: thread moved]


I was pointed to a mutation in the ITPR3 gene. This gene codes for a protein consisting of a calcium channel and a so-called Inositol 1,4,5-triphosphate receptor of type 3 (IP3R3); there are also type 1 and 2 receptors. Amongst others, Inositol 1,4,5-triphosphate binds to this receptor and thus, the calcium channel is activated.

I searched for some papers about this gene and, to my knowledge, there are not so many publications and knowledge about IP3R3 (there is a bit more about IP3R1 and IP3R2 and their dysfunctions).

But I thought about two points:
First, the IP3R3 (including calcium channel) seems to play a role in ATP production, amongst others, and problems with this receptor lead to an impaired function in pyruvate dehydrogenase (see [1]). Now, Fluge et al observed impaired pyruvate dehydrogenase in people with ME.

Second, calcium channels play a role with respect to mast cells, too (see [2] which was provided by Dr. Afrin - many thanks!). The question arose since IP3R3 plays a role in autophagy/apoptosis, too (see [3]), and the authors of [4] mention:
Pathogenetically, MCAD denotes a group of polygenic MC disorders (Molderings 2015, 2016) characterized by aberrant release of variable subsets of MC mediators and also an accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (SM and MCL) or morphologically ordinary MCs due to decreased apoptosis (MCAS; Kohno et al. 2005;Aichbergeretal. 2009;Karlbergetal.2010a).
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(Markings by me.)

Whether IP3R3 is connected to mast cells explicitly, I cannot say. But maybe it can be hypothesized. Dr. Afrin was very kind and replied to my question saying it would be an interesting research topic whether people with calcium channelopathies have MCAD issues more often. Due to the role of calcium channels in mast cell regulation one might hypothesize that.

Does anyone know of a role of ITPR3 mutations (or other mutations of genes coding ion channels) in ME? Has anyone any knowledge about its connections to mast cell dysfunctions?

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911450
p. 4: "Here, we have identified a fundamental cellular metabolic control mechanism involving activity of the endoplasmic reticulum-localized inositol trisphosphate receptor (InsP3R) Ca2+ release channel. In the absence of basal constitutive low-level Ca2+ signaling by the InsP3R, cells become metabolically compromised as a result of diminished Ca2+ uptake by mitochondria. Constitutive mitochondrial Ca2+ uptake of InsP3R released Ca2+ is fundamentally required to maintain sufficient mitochondrial NADH production to support oxidative phosphorylation in resting cells. Absence of this Ca2+ transfer results in inhibition of pyruvate dehydrogenase and activation of AMPK, which activates pro-survival autophagy by an mTOR-independent mechanism. These results reveal a here-to-fore unexpected and fundamentally essential role for constitutive low-level InsP3R Ca2+release to mitochondria to maintain viable levels of oxidative phosphorylation."

[2] https://www.ncbi.nlm.nih.gov/books/NBK45036/

[3] https://www.ncbi.nlm.nih.gov/pubmed/20383523

[4] https://www.ncbi.nlm.nih.gov/pubmed/27132234
 
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Inara said:
Dr. Afrin was very kind and replied to my question saying it would be an interesting research topic whether people with calcium channelopathies have MCAD issues more often.
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Thank you for posting this @Inara and I bookmarked it as well. The science is way above my head and I won't even pretend that I can understand it!

I quoted one thing that you wrote that stood out to me. I have a calcium channelopathy (the N-type CA+ Channel Autoantibody) and I also have MCAS. I know there has to be a link between the two but I don't really understand what it is! Did you contact Dr. Afrin directly to ask him this question or is he your treating doctor? Did he say that there is a link or only that it would be interesting to study further? I wasn't sure if I understood but my guess is that the potential link has not been studied yet.

I have never spoken to Dr. Afrin but my doctor consulted with him on the phone re: my case in 2015 when I was in the hospital, having anaphylaxis to all food, and we were basically out of ideas re: how to stop it at that time. I did not know (until 2016) that I had the CA+ Channel Autoantibody so it was not part of the discussion that my doctor had with Dr. Afrin.
 
Dear @Gingergrrl, I wrote Mr. Afrin my question and he answered. So I am not a patient of his, just interested in the research.

I asked about the role of calcium channels in MCAS, in particular about IP3R3, since it seems to play a role in autophagy and apoptosis. I understood Molderings' et al publication such that mast cell issues might also arise due to decreasesd mast cell apoptosis, and I wondered if calcium channels - and the IP3R3 one, too - might play a role in mast cell apoptosis, too. So the idea was, a calcium channel dysfunction could lead to mast cell proplems.

The paper Mr. Afrin referenced (see [2]) - I haven't read it completely yet - speaks about calcium channels and mast cells. Mr. Afrin said one might hypothesize whether calcium channelopathies may lead to MCAS, but that he doesn't know of a publication showing this explicitly, and therefore this could be a research topic. No, he didn't say there's a link, just that there might be one (which would have to be studied more thoroughly).

For me, both questions are very interesting, therefore I wrote them here - maybe there are more answers. I was very happy to receive Mr. Afrin's reply. Although I pity a bit I can't do research myself. :)
 
Inara said:
But I thought about two points:
First, the IP3R3 (including calcium channel) seems to play a role in ATP production, amongst others, and problems with this receptor lead to an impaired function in pyruvate dehydrogenase (see [1]). Now, Fluge et al observed impaired pyruvate dehydrogenase in people with ME.

Second, calcium channels play a role with respect to mast cells, too (see [2] which was provided by Dr. Afrin - many thanks!). The question arose since IP3R3 plays a role in autophagy/apoptosis, too (see [3]), and the authors of [4] mention:
Click to expand...
Hi Inara, the science is beyond me and I can't open all the links, so just wondered if you have contacted the Tronstad Lab, as Professor Karl Tronstad was involved with the 2016 paper by Fluge (https://insight.jci.org/articles/view/89376) and I believe his team got further funding from the Norwegian Research Council to investigate this. He is attending the Invest in ME Research Biomedical Research into ME Colloquium (BRMEC8) this year and presenting at the conference (IIMEC13), as is mast cell researcher, Professor Theoharis Theoharides (http://www.investinme.eu/IIMEC13-news-180202.shtml) and Professor Don Staines from NCNED (http://www.investinme.eu/IIMEC13-news-180208.shtml but the URLs for NCNED seem to have changed and I notice that under the subheading 'Full Members', it says that "Dr Helene Cabanas is a young emerging researcher who specializes in understanding calcium pathway signaling and their implications in physiological and pathophysiological processes." (https://www.griffith.edu.au/menzies...ditions/neuroimmunology-and-emerging-diseases).

 
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