Naltrexone, NK cells and the calcium ion channel research

[Gingergrrl]

Before I reply, I am tagging @Inara b/c am not sure if she saw this thread and she is also very interested in calcium issues (but is much smarter than me )

For instance, this is a nice article on T lymphocytes, and they mention the type of calcium channel you have been referring to (TRPs).

The type of calcium channel that I was referring to is the "N-type calcium channel" (not the L-type) which is also known as VGCC or "voltage gated calcium channel". I looked at the article you linked but was instantly over my head in trying to understand it. What does "TRP" mean?

I do not know the ME/CFS literature on calcium channel autoantibodies. I am aware of reports of a few autoantibodies such as specific adrenergic receptors and acetylcholine receptors, and ANA.

I'm not sure if there is ME/CFS literature on calcium channel autoantibodies and this is part of what I am trying to understand. In addition to (myself) testing positive 2x for the N-type calcium channel autoantibodies on Mayo Panels, I also test positive for autoantibodies to everything that you mentioned above alpha & beta adrenergic receptors, anti-muscarinic/cholinergic receptors, and positive ANA 1:160, speckled pattern (prior to my treatment).

My doctor and I came to the conclusion in mid-2016 that I do not have ME/CFS after all (even though every doctor that I saw starting in 2013 gave me a "CFS" diagnosis in the U.S.). But recently, I read that the ICC criteria for ME/CFS contain a section on "ion transport issues" and now there is so much research (mostly from Australia and Germany) re: calcium channels and autoantibodies.

I belong to a private group on FB for people w/the N-type CA+ Channel Autoantibody and almost 100% of the members also have POTS and many were initially given ME/CFS diagnoses like I was. So there is a great deal of overlap that no one is putting together IMO. It definitely won't be me putting the pieces together b/c I have no science background but I am closely following it (and those smarter than me who are able to make sense of it all)!

@Gingergrrl I think that the research group in Australia are in the stages of proposing using their clamp device as a biomarker, in terms of to the TRMP3 genetic defect (SNP) - but I don't have all the literature around it at the moment. Their specialty is neuro-immune, I think.

That is really interesting and I am wondering if people who test positive for this calcium defect will be considered to have ME/CFS regardless of their symptoms or if people would need to have BOTH the biomarker AND the symptoms in the ICC (or another chosen criteria)?

I did recently see a video of Dan Peterson (a new working group) who said he feels there are several different disorders or diseases involved in what is currently known as M.E. and CFS.

I now agree with Dr. Peterson but had no idea that was his view until I read your quote. Do you know why he feels ME/CFS is several different disorders or diseases? The reason I now do is because I have been on PR since 2014 and literally spoken to hundreds of members and the differences between how they got ill, what they test positive for, what symptoms they have, and what treatments helped them are so vastly different that I don't see how it is just one disease. That is just my personal opinion and I don't mean it to be controversial in any way (and in the end, I am totally open to being wrong)!

 

[Marylib]

@Gingergrrl I was listening to the video's on this site. I may have misinterpreted or mischaracterized what Dr Peterson said, so maybe this will help you.

https://www.youtube.com/channel/UC5ZeQTi3bBr3oaSeubCz_Nw

 

[skandar]

The type of calcium channel that I was referring to is the "N-type calcium channel" (not the L-type) which is also known as VGCC or "voltage gated calcium channel". I looked at the article you linked but was instantly over my head in trying to understand it. What does "TRP" mean?

One major category of calcium channels are the voltage gated calcium channels
(VGCC). Within this category there are different types of voltage gated calcium channels with different behavior.
"VGCC is divided into five types: L, P/Q, N, R, T depending on tissues and pharmacological properties[7]"
A review is here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360501/

TRPs are "transient receptor potential" channels, some of which are calcium channels. There are 6 known families of TRP ion channels, each with different properties. TRPM3 is one member of the TRPM subfamily, and it (TRPM3) is the channel at the focus of this thread begun by @Marylib.
It is very confusing, and added to that, there are a few typos in this thread when typing the acronym, "TRPM".

This review on TRPs, though in 2006, is by one of the world's leading experts, David Clapham.
https://www.ncbi.nlm.nih.gov/pubmed/16460286
However, what we have learned about TRPM3 is more recent than this review, but I cite it here anyway for some of the "sciencey" types that come by PR now and then.

@Gingergrrl , your autoantibody panel results are fascinating. I did not realize there are folks with so many autoantibodies to these channels. Thanks for sharing.

 

[heapsreal]

But Open Medicine Foundation is now recruiting for patients with connective tissue problems, as this something that keeps popping up in the patient population - along with the structural defects like cervical cranial instability.

So is this possibly involved in EDS as well as pots/oi??

 

[Marylib]

@skandar Sorry about those typo's. I have serious cognitive issues. Thanks to @Mary for helping clean all this up.

 

[Mary]

Thanks to @Mary for helping clean all this up.

I think you're thinking of a different thread

 

[skandar]

@skandar Sorry about those typo's. I have serious cognitive issues. Thanks to @Mary for helping clean all this up.

Oh gosh, of course I understand typos, and with this disease? It's running a marathon just to type an idea.
I've made so many typos on Twitter, that the people who know I'm a scientist have probably muted me because they can't trust what I write. Once I tried to explain how the NK activity assay worked since we've done similar kinds of activity assays in my lab (I had to shut lab down bc of this disease) - that was a disaster bc I was too fatigued and tried to type on my iphone.

After 23 years with ME, my brain is finally shot, so I hear you @Marylib (it has proven to be progressive in my case)

 

[Marylib]

Hi everyone. Thanks for your kind words.

Here is a radio interview with Sonya from the Griffith Uni group. Also in the interview is a mother of a very sick child. Maybe this will help explain some things, though Sonya says another paper is out in two weeks, along with a possible pharmaceutical intervention:

https://www.abc.net.au/radio/newcastle/programs/mornings/chronic-fatigue/11645618

 

[Gingergrrl]

@Gingergrrl I was listening to the video's on this site. I may have misinterpreted or mischaracterized what Dr Peterson said, so maybe this will help you.

Thx and I just listened to the short video w/Dr. Peterson and I don't think you mischaracterized it at all and it sounds like he now believes that we are dealing with multiple different diseases and treatments.

One major category of calcium channels are voltage gated calcium channels (VGCC). Within this category there are different types of voltage gated calcium channels with different behavior. "VGCC is divided into five types: L, P/Q, N, R, T depending on tissues and pharmacological properties[7]"

The VGCC are the only ones I am familiar with b/c of my autoantibody. As far as I can tell, the only commercial tests (at Mayo) are for the N-type and the P/Q type autoantibodies. I'm assuming the others can be tested within a research setting but not for the public. I am positive for the N-type but not the P/Q type (on Mayo Panels).

@Gingergrrl, your autoantibody panel results are fascinating. I did not realize there are folks with so many autoantibodies to these channels. Thanks for sharing.

As far as I know I am only positive for the N-type. I have tons of other autoantibodies but they are not against the calcium channels. I am still trying to learn as much as I can about all of this. Are the alpha & beta adrenergic and anti-muscarinic/cholinergic autoantibodies also against these channels? I also test positive for anti GAD65 and the two Hashimoto's autoantibodies.

I think you're thinking of a different thread

I'm not sure which thread they were thinking of... but either way, we want to thank you for all of your hard work @Mary

I've made so many typos on Twitter, that the people who know I'm a scientist have probably muted me because they can't trust what I write. Once I tried to explain how the NK activity assay worked since we've done similar kinds of activity assays in my lab

I am so impressed with all of the scientists on PR (even if you are not currently working due to illness) and the knowledge base, for us non-science people, is so helpful. You could make up a name for a calcium channel (the "abc123 channel" and I would believe you that it was real

Maybe this will help explain some things, though Sonya says another paper is out in two weeks, along with a possible pharmaceutical intervention:

I listened to the video but missed the part about the possible pharma intervention. Did she say what it was and if it related to the calcium channel research?

 

[skandar]

As far as I know I am only positive for the N-type. I have tons of other autoantibodies but they are not against the calcium channels. I am still trying to learn as much as I can about all of this. Are the alpha & beta adrenergic and anti-muscarinic/cholinergic autoantibodies also against these channels?

No, all these autoantibodies will be different (their epitope will differ). The reason is that the alpha & beta adrenergic receptors, and the Ach receptors bind different ligands and autoantibodies against these receptors will be a different a.a. sequence from any of the autoantibodies to any of the different types of calcium channels.

 

[Wishful]

I was on LDN for more than 4 months and did not have conclusive benefits. It seems to have had an impact on my neuropathic pain, but it’s still not clear if it stopped for good or will come back again. Other than that, not much changed while I was on it.

My experience, being on it for a year or so, was that it blocked my neuropathic pain very effectively, which was a big improvement in my quality of life. Taking LDN allowed me to enjoy going for long hikes in the woods, or bike rides, and other activities. I didn't realize how crippling the chronic pain was until it was blocked. After a year or so of LDN, I no longer needed it; the neuropathic pain was gone. It's been a couple of years since I stopped LDN, and the pain hasn't returned. I can't be completely sure that the LDN caused the 'cure', but I think it's quite likely.

I'd certainly call LDN's effect on me as 'conclusive benefits'.

 

[Gingergrrl]

No, all these autoantibodies will be different (their epitope will differ).

That part makes sense to me (and I Googled "epitope" to be sure!) and it sounds like each autoantibody has different binding sites and affects different systems in the body.

The reason is that the alpha & beta adrenergic receptors, and the Ach receptors bind different ligands and autoantibodies against these receptors will be a different a.a. sequence from any of the autoantibodies to any of the different types of calcium channels.

I didn't understand this sentence and keep re-reading it. Can you explain it in completely non-science terms? What does "different a.a. sequence" mean? Do alpha & beta adrenergic receptors and anti muscarinic/cholinergic receptors relate to each other and/or relate to anti calcium channel autoantibodies? I had assumed that they were all completely different and that me having all of them just meant that my entire system was in "autoimmune chaos" (as my doctor called it) vs. that they related to each other?

 

[Marylib]

So it seems the group at Griffith University are collecting data and samples from patients (including severe) who have been using naltrexone. Calling all Aussies! Or those with specialists who want to collaborate internationally, perhaps.


𝗡𝗖𝗡𝗘𝗗 𝘀𝗲𝗲𝗸𝗶𝗻𝗴 𝗠𝗘/𝗖𝗙𝗦 𝗽𝗮𝗿𝘁𝗶𝗰𝗶𝗽𝗮𝗻𝘁𝘀 𝘄𝗵𝗼 𝗮𝗿𝗲 𝗰𝘂𝗿𝗿𝗲𝗻𝘁𝗹𝘆 𝘁𝗮𝗸𝗶𝗻𝗴 𝗟𝗼𝘄 𝗗𝗼𝘀𝗲 𝗡𝗮𝗹𝘁𝗿𝗲𝘅𝗼𝗻𝗲 (𝗟𝗗𝗡)
NCNED would like to hear from ME/CFS patients who are currently taking LDN. If you are a ME/CFS patient taking LDN and would consider participating in a research program please contact NCNED.
For further information please email ncned@griffith.edu.au or call (07) 56789283.

 

[skandar]

That part makes sense to me (and I Googled "epitope" to be sure!) and it sounds like each autoantibody has different binding sites and affects different systems in the body.

I didn't understand this sentence and keep re-reading it. Can you explain it in completely non-science terms? What does "different a.a. sequence" mean? Do alpha & beta adrenergic receptors and anti muscarinic/cholinergic receptors relate to each other and/or relate to anti calcium channel autoantibodies? I had assumed that they were all completely different and that me having all of them just meant that my entire system was in "autoimmune chaos" (as my doctor called it) vs. that they related to each other?

My writing got sloppy as I fatigued, sorry about that.
Adrenergic receptors (AR) and acetylcholine receptors (AchR) are different. They are located throughout the body and their primary known function is regulating the autonomic nervous system (ANS). As you noted, within these two major families (superfamilies) there are different types of receptors (alpha, beta, AND nicotinic, muscarinic). The AR's are G-coupled protein receptors. This means when their ligand (adrenaline or noradrenaline) binds, it triggers a number of changes in the cell, and these changes ultimately cause increases or decreases in intracellular calcium, usually from the cell's endoplasmic reticulum or the sarcoplasmic reticulum (if in striated muscle). Many drugs target AR's to regulate blood pressure, heart rate, or to control bronchial smooth muscle in the case of asthma.

AchR's are on nerve cells or muscle cells (primarily) and bind the ligand acetylcholine, As you noted there are nicotinic AchR's and muscarinic AchR. nAchR's are ligand gated ion channels where there is a conformational change when acetylcholine binds that allows the influx of sodium. mAchR are G-coupled protein receptors and so they act to alter ion flux through indirect or second messengers. AchR's are also a drug target just like AR's.

So yes, all the autoantibodies you have for each of these receptors are unique, including your antibodies to the N type voltage-gated calcium channel. My explanation of these receptors is oversimplified.

Epitopes are the part (or the amino acid sequence) of a protein that an antibody binds to. It usually has a sequence of about 6 amino acids (a.a.). This short sequence is partly why there are so many false positives when trying to identify the presence of an antibody in a person's sample of fluid or tissue. And I believe this is why clinicians use antibody panels to help them in diagnosis.

 

[Gingergrrl]

My writing got sloppy as I fatigued, sorry about that.

Thank you so much for all of the information @skandar and your writing is not sloppy at all! I just have no science background (prior to getting ill myself and trying to learn all of this stuff about my own case).

Adrenergic receptors (AR) and acetylcholine receptors (AchR) are different. They are located throughout the body and their primary known function is regulating the autonomic nervous system (ANS).

I did know that the Adrenergic receptors (AR) and acetylcholine receptors (AchR) are different. What I didn't get is that you just said that they both regulate the autonomic nervous system and I had thought the AR regulated the ANS and the AchR regulated neuromuscular stuff (like muscle weakness)?

As you noted, within these two major families (superfamilies) there are different types of receptors (alpha, beta, AND nicotinic, muscarinic).

If I noted all of that than I am smarter than I thought LOL ... All I know is that I have autoantibodies to the alpha, beta, and muscarinic/cholinergic (but not to the nicotinic receptors). Plus I have the N-type calcium channel autoantibodies, anti GAD65, and the two Hashimoto's Abs. What did you mean by "superfamilies" (or are those the same as two groups that you mentioned above- the AR and AchR)?

The AR's are G-coupled protein receptors. This means when their ligand (adrenaline or noradrenaline) binds, it triggers a number of changes in the cell, and these changes ultimately cause increases or decreases in intracellular calcium, usually from the cell's endoplasmic reticulum or the sarcoplasmic reticulum (if in striated muscle). Many drugs target AR's to regulate blood pressure, heart rate, or to control bronchial smooth muscle in the case of asthma.

So the AR's cause changes in intracellular calcium? My (very limited) understanding was that my autoantibodies to the AR's relate to why I have POTS and autonomic problems but I did not know that they relate to calcium issues, too. I belong to a group on FB with people who all have the N-type Calcium Channel autoantibody and almost every single person also has POTS. Is this the connection (the AR autoantibodies)? I am one of the only people in that group who has been tested for the adrenergic receptor autoantibodies.

AchR's are on nerve cells or muscle cells (primarily) and bind the ligand acetylcholine, As you noted there are nicotinic AchR's and muscarinic AchR. nAchR's are ligand gated ion channels where there is a conformational change when acetylcholine binds that allows the influx of sodium.

I did know that the AchR's relate to muscle cells but I thought the autoantibodies caused calcium channel issues (but you said they regulate sodium issues)? I apologize that my understand of all of this is still so low

So yes, all the autoantibodies you have for each of these receptors are unique, including your antibodies to the N type voltage-gated calcium channel. My explanation of these receptors is oversimplified.

It's not oversimplified at all for me and I really appreciate it.

Epitopes are the part (or the amino acid sequence) of a protein that an antibody binds to. It usually has a sequence of about 6 amino acids (a.a.). This short sequence is partly why there are so many false positives when trying to identify the presence of an antibody in a person's sample of fluid or tissue. And I believe this is why clinicians use antibody panels to help them in diagnosis.

So autoantibodies bind to a sequence that is very short and that is why there are false positives? Is this the case with all autoantibodies or more so with the common ones vs. rare/obscure ones?

 

[skandar]

I did know that the Adrenergic receptors (AR) and acetylcholine receptors (AchR) are different. What I didn't get is that you just said that they both regulate the autonomic nervous system and I had thought the AR regulated the ANS and the AchR regulated neuromuscular stuff (like muscle weakness)?

The nAchR is necessary for neuromuscular function, skeletal muscle. They are located on the NMJ called the motor end plate. They initiate depolarization of the muscle membrane. mAchR are located on nerves.

It's not oversimplified at all for me and I really appreciate it.

What I meant here is that all this is much more complicated than I am writing. You’ll find this is true if you go and try to google any of these structures.

 

[skandar]

So autoantibodies bind to a sequence that is very short and that is why there are false positives? Is this the case with all autoantibodies or more so with the common ones vs. rare/obscure ones?

All antibodies bind to short amino acid sequences on their target proteins.

 

[skandar]

I did know that the AchR's relate to muscle cells but I thought the autoantibodies caused calcium channel issues (but you said they regulate sodium issues)?

nAchR are on skeletal muscle fibers (the motor end plate) and mAchR are throughout the CNS. Please see posts above on how these two types of receptors differ in how they function. Autoantibodies against calcium channels, if in great enough numbers (and for long enough) will cause function problems with the specific type of calcium channel they are targeting. nAchR autoantibodies, if in great enough numbers for a period of time will cause problems with muscle depolarization.

Superfamilies are just many different types of a protein that have different functions, but retain some core features of a certain protein. I am an over-explainer as u can see, so please google or use Wikipedia to look up superfamily. You'll get a better explanation that what I can manage

I’m not sure autoantibodies always wreck havoc on cell function but in many diseases they cause significant problems and f they are abundant enough for a long enough time period, and where they bind.

 

[EtherSpin]

The reasearch may be good, but I'm a bit leery when they mischaracterize the symptoms of ME/CFS.

great point. I know maybe 20 people who are either on LDN or have been on it for a significant course in the past and none of them took it FOR pain , I'm not really aware of any of them getting pain reduction from it, just things like a little more mental clarity, faster recovery after exertion, temperature tolerance, deeper sleep.

 

[Rufous McKinney]

that the people who know I'm a scientist have probably muted me because they can't trust what I write.

I've entirely evaporated from the scientific world from whence I came. And did anybody notice?