Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from ME/CFS patients

[Gingergrrl]

The researchers found lowered intracellular calcium. Lowering it further (e.g. by blockage) is maybe not the right thing to do...

This is my feeling as well and it seems to me (regardless what this illness, or group of illnesses, will ultimately be called), that people who *improve from Calcium Channel Blockers are in a different subgroup from those who worsen or cannot tolerate CCB's (like me). I am so glad that the Australian research team is studying this issue.

L-type calcium channels and TRPM3 are different (how exactly, please don't ask ).

Don't worry, I was not going to ask, but I wish I had your brain ... One thing I still don't have an answer to is how they test if someone has an autoantibody to the L-type Calcium Channel? It seems that the L-type autoantibodies can only be tested for within research and that there is no commercial test (like there is for the N-type and P/Q type). I wonder about this for practical reasons, for example Propofol (anesthesia) blocks the L-type calcium channel (but how would you know if you have autoantibodies to the L-type if there is no test, so it is probably better to just completely avoid this anesthesia in absence of having this info).

As you know, in my case another calcium channel is affected, so that I start to think that many ways lead to Rome, i.e. different (let me call it) calcium channelopathies maybe lead to similar symptoms, maybe even to very similar pathomechanisms. Because if one part in the calcium signaling cascade is affected, the rest may be too.

This makes sense to me and maybe some day there will be an illness called "Calcium Channelopathy" that is then broken into subgroups depending on which channel is affected and for what reasons and what symptoms it causes. I am told that I have a calcium channelopathy but in practical terms, the only illness I know of that matches with this is "LEMS" (which is a decent match for my symptoms prior to treatment but definitely not a complete or full match).

This isn't known yet. It could be autoimmunity, it could be "mutated" channels, it could be something else (viruses?).

Thank you and that makes total sense (that it could be a mutation, virus, etc, and not only autoimmunity). I am going to remember this part now.

Not many human calcium channels can be researched, human NK cells seem to be suited (at least this is how I understood a researcher who explained to me the tests they will be doing on "my" calcium channel).

So do all cells have Calcium Channels but, for whatever reason, the NK cells are better suited to be studied for these types of tests/research? (sorry if this is a stupid question )

It would make sense to call a calcium channel that produces a dysfunctional calcium signal (and which leads to symptoms/disease) a "calcium channelopathy" , wouldn't it?

It makes sense to me but I was not sure if it was accurate. Prior to 2016 when I was diagnosed with this autoantibody on Mayo test, I had never heard of any of these terms and it was like learning a new language (that I am still learning )

 

[Inara]

that people who *improve from Calcium Channel Blockers are in a different subgroup from those who worsen or cannot tolerate CCB's (like me).

My feeling is this can be complicated. Some substances that block one calcium channel trigger another one in the cell. E.g. caffeine - it inhibits IP3R, but triggers RyR. As far as I know there is no substance that addresses IP3R alone, for instance. (But I'd be realky happy to be corrected!)

I think knowledge about longtime consequences of meds that block/trigger ion channels is very restricted. One reason certainly is that it's really complex. After what I have read about calcium signaling, I am not sure if a human should take meds long time that may change the calcium signal in any way. But that's just my opinion. And often we don't have any choices. (E.g., do I mess with calcium channels, or sodium/potassium channels, or do I have severe pain?) But I think addressing dysfunctional calcium channels has a lot of therapeutic potential in the future.

One thing I still don't have an answer to is how they test if someone has an autoantibody to the L-type Calcium Channel?

I have not enough knowledge about these things, but certainly someone else here does.
I agree it would be interesting in a clinical setting. Its non-existence may implicate it's still research (i.e. complex)? I don't even know how you can suspect L-type issues, i.e. which symptoms would be present?

and maybe some day there will be an illness called "Calcium Channelopathy" that is then broken into subgroups depending on which channel is affected and for what reasons and what symptoms it causes.

"Calcium channelopathy" (or more general, ion channelopathy) is already in use, at least here it seems.

So do all cells have Calcium Channels but, for whatever reason, the NK cells are better suited to be studied for these types of tests/research? (sorry if this is a stupid question )

This is not a stupid question! Yes, every cell has calcium channels (and other ion channels). The researcher briefly explained why they use NK cells, but I forgot the details. ☹ I remember they use fibroblasts because they are easily available and easily cultured (or so) and NK cells because...they are easily available. ad isolated? I would have to ask again, which I will I think because it interests me.

 

[Gingergrrl]

My feeling is this can be complicated. Some substances that block one calcium channel trigger another one in the cell.

This did not even occur to me and I assumed that something either blocked the calcium channel or opened it (but not that one substance could do both ). And I'm not sure if "open" is the proper term but hopefully you know what I mean.

After what I have read about calcium signaling, I am not sure if a human should take meds long time that may change the calcium signal in any way. But that's just my opinion.

Does "calcium signaling" mean anything that alters the amount of calcium in the cell (blocks, opens, damages, etc)? Are there meds that do this besides "calcium channel blockers"?

But I think addressing dysfunctional calcium channels has a lot of therapeutic potential in the future.

I agree with you and in my case, treatments for autoimmunity were the game changer (in addition to treatments for MCAS). But the autoimmune treatments stopped (or reduced?) the pathogenic mechanism of the calcium autoantibodies, which for me was muscle weakness and breathing weakness, and for the other autoantibodies was POTS. I don't know that it directly changed the calcium channels but maybe it did?

I have not enough knowledge about these things, but certainly someone else here does. I agree it would be interesting in a clinical setting. Its non-existence may implicate it's still research (i.e. complex)? I don't even know how you can suspect L-type issues, i.e. which symptoms would be present?

The Mayo panels only test for the P/Q and N-type autoantibodies, and not the L-type, which is why I assumed that there was no commercial test. I avoid ALL calcium channel blockers, even if my Google research tells me that they only block the L-type, b/c without a test, I don't actually know if I have autoantibodies for the L-type. So I am avoiding Propofol (for my colonoscopy in August) which is totally fine and it is not needed. But some day if I am told that it is needed, I am not sure what I would do?

"Calcium channelopathy" (or more general, ion channelopathy) is already in use, at least here it seems.

Do you mean that the term "Calcium Channelopathy" refers to a specific disease or illness now (in current medicine)? I thought it explained a medical process that occurs within the cell but it was not connected to a specific disease? Is having it a bio-marker of something?!

This is not a stupid question! Yes, every cell has calcium channels (and other ion channels). The researcher briefly explained why they use NK cells, but I forgot the details. ☹

I wasn't sure if every cell had calcium channels but assumed they did. I never studied chemistry as you can tell

 

[Inara]

This did not even occur to me and I assumed that something either blocked the calcium channel or opened it (but not that one substance could do both ).

This is a misunderstanding I fear. I meant if one substance e.g. inhibits calcium channel of type A, then it might "trigger" a calcium channel of another type B. Not that one substance can inhibit and trigger the same calcium channel at the same time. Although there are "substances" that can do that in case of e.g. ligand gated channels (calcium itself for instance, and IP3; in that case, the amount of Ca ions and/or IP3 molecules decides whether the channel opens or closes; but with substance I meant things like heparin, caffeine, dexamethesone, other meds etc).

Does "calcium signaling" mean anything that alters the amount of calcium in the cell

I read more about ligand-gated calcium channels, so the following is wrt. that. I think in case of voltage-gated channels, "amount" (meaning the magnitude of voltage or a voltage range) plays a crucial role; but how exactly I annot say. And if the quality of the signal (meaning a certain amplitude or frequency) is important, too, I don't know. I don't know if voltage-gated channels are truly an "off-on system", but they seem to be like a "switch".
Calcium signaling reminded me a bit of machine language (i.e. 0, 1), although it is more finely tuned. Each 0-1-combination contains a certain information which the machine can understand and then react accordingly. There are redundancies and check sums to make the communication more reliable. I understand a calcium signal to be comparable: Frequency and amplitude decode a certain "command" to a cell; there is redundancy and the like to allow some flexibility/reliability. I understood that the different calcium channels can work together in producing a signal.

Extracelluar and intracellular calcium levels play a role in the sense that you need Ca ions to form the signal (and a certain amount to open/close them). E.g. in order to fill the endoplasmic reticulum with Ca, there are channels and pumps that get extracellular calcium inside the cell and then inside the ER, and the ER "produces" Ca signals. Ca is toxic for the cell, so Ca signals have a small range (in nm) and are short-lived, and therefore organelles can move to each other in close proximity.

I am not sure if you can influence ligand-gated calcium channels by supplementation. In case of voltage-gated channels that might be so (but I have no knowledge and no personal experience about that).

Do you mean that the term "Calcium Channelopathy" refers to a specific disease or illness now (in current medicine)?

I've understood that "calcium channelopathy" refers to dysfunctions of calcium channels that lead to disease. I don't know if it's official (it was just on a Center for Rare Diseases website). I don't think there's an ICD code? So I think the resulting diseases may be coded. Btw, do you have a neuropathy?

 

[Gingergrrl]

@Inara I'm not sure if my replies are adding anything useful but am going to attempt...

This is a misunderstanding I fear. I meant if one substance e.g. inhibits calcium channel of type A, then it might "trigger" a calcium channel of another type B. Not that one substance can inhibit and trigger the same calcium channel at the same time.

Thanks for explaining that. Would that mean that something that blocks the N-type channel (for example) might not block the L-type (and vice versa)?

Although there are "substances" that can do that in case of e.g. ligand gated channels

I just Googled "ligand" (for about the millionth time since 2016 when I learned that I had this autoantibody) but literally cannot retain the meaning of the word. I guess it is the opposite of what I have? (I don't mean that I don't have ligand channels but I mean the opposite of the type that I have autoantibodies against)?

I am not sure if you can influence ligand-gated calcium channels by supplementation. In case of voltage-gated channels that might be so (but I have no knowledge and no personal experience about that).

When I was first diagnosed with this autoantibody by Stanford, the Neuro (who was an assistant) told me that it was possible to take calcium as a supplement to help against the autoantibody that I had. However, she did not specify an amount of calcium and it all seemed like speculation to me. But she implied that taking calcium could be helpful in my situation. I don't know that other Neuros would agree and I suspect you'd have to take a HUGE dose to make any difference?!

I've understood that "calcium channelopathy" refers to dysfunctions of calcium channels that lead to disease. I don't know if it's official (it was just on a Center for Rare Diseases website). I don't think there's an ICD code? So I think the resulting diseases may be coded. Btw, do you have a neuropathy?

I don't think that there is an ICD code for "calcium channelopathy" like there is for LEMS (but I could be wrong). I know there are some potassium channelopathies as well (I think "periodic paralysis disorder" and some others). I researched all of this a few years ago but clearly did not retain it.

To your last question, it is unclear if I have neuropathy and I never did a biopsy for "SFN" (small fiber neuropathy) but I did have neuropathy on the testing I did at Stanford (QSART) which showed an abnormal sweat response and "long branch neuropathy" to my feet. This was odd to me b/c I have no issues with my feet vs. my right arm which was damaged by Levaquin. But my main doctor considered "autonomic neuropathy" (which has many similar names like "autoimmune neuropathy" etc) to be one of my diagnoses based on my abnormal TTT, QSART, and other autonomic tests that I can't even remember the names of (from early 2016 before I started treatment).

 

[pattismith]

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

• july 2019

Abstract

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix.
General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency.

We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.
...
Results
Clinical findings

The probands are eight unrelated individuals with a symptom complex comprising moderate-to-severe global developmental delay (eight individuals), hypotonia or mixed tone abnormality (eight individuals), electrographically confirmed epilepsy (seven individuals), and/or variable minor anomalies (Table 1).

Seizures corresponded to several clinical types (absence, generalized tonic-clonic, infantile spasms, and subclinical, including electrographic status epilepticus of sleep), were noted in infancy or early childhood, and were generally responsive to standard medical management. Electroencephalography showed nonspecific epileptiform activity. Brain MRI was normal in six individuals, and showed nonspecific volume loss in two individuals. Other associated anomalies, each observed in a minority of probands, included: Strabismus (four individuals), scoliosis (three individuals), talipes equinovarus (two individuals), athetoid movements in infancy (two individuals), C1 vertebral anomalies (two individuals),...

 

[Murph]

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

• july 2019

Abstract

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix.
General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency.

We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.
...
Results
Clinical findings

The probands are eight unrelated individuals with a symptom complex comprising moderate-to-severe global developmental delay (eight individuals), hypotonia or mixed tone abnormality (eight individuals), electrographically confirmed epilepsy (seven individuals), and/or variable minor anomalies (Table 1).

Seizures corresponded to several clinical types (absence, generalized tonic-clonic, infantile spasms, and subclinical, including electrographic status epilepticus of sleep), were noted in infancy or early childhood, and were generally responsive to standard medical management. Electroencephalography showed nonspecific epileptiform activity. Brain MRI was normal in six individuals, and showed nonspecific volume loss in two individuals. Other associated anomalies, each observed in a minority of probands, included: Strabismus (four individuals), scoliosis (three individuals), talipes equinovarus (two individuals), athetoid movements in infancy (two individuals), C1 vertebral anomalies (two individuals),...

My gut feel on this: the diseases and pathologies resulting from these mutations share relatively little with the symptoms of me/cfs. Certainly seizures aren't common. Perhaps hypotonia is similar to muscle weakness.

 

[SlamDancin]

I still don’t know why, but I actually enjoy taking my Naltrexone 25-50mg every day now. It still seems to lift some of the heavy fatigue. I think it really deserves to be tested in a pilot study.

 

[Wishful]

It still seems to lift some of the heavy fatigue.

Is it actually reducing fatigue, or just reducing pain? I know that neuropathic muscle aches made it harder to do anything, which felt somewhat like fatigue. LDN blocked those aches, which made me feel more energetic. It's hard work moving those legs when they keep sending (imaginary) pain signals.

 

[SlamDancin]

@Wishful Almost impossible to tell right? However this is different from any effect
I ever got from LDN and it’s an immediately noticeable effect, within minutes of taking the first dose of the day.

 

[Wishful]

Yes, it is hard to tell the difference. I think it's good to know that it is confusing, so we don't go overboard on one theory (fatigue or chronic neuropathic pain) but rather stay open to other possibilities.

Before limited resources are put into a pilot study, you should first try to find out if the effect works for more PWME. I've found two things that work great for me, but don't work for anyone else, so not much point in a pilot study...

 

[SlamDancin]

Well, point taken, but no one is running out and doing pilot studies based on what I think anyways. I actually think joint hypermobility, craniocervical blockages and IC hypertension are likely more fundamental causal problems for more pwME than whatever the Naltrexone is doing for me I just noticed it helps. Also I now can tell that where I thought my jaw was supposed to be was actually completely out of wack and it took a year of muscle manipulation, basically the theory that you can’t stretch connective tissue so you have to stretch the muscle around it to heal these issues unless you do the drastic surgeries, before I finally could tell and it feels natural to do so. So anyways I’m happy that’s being studied so thoroughly now finally.

Fittingly, I think this week I should start a new splint device for my jaw to keep this in proper place and I believe a significant amount of problems will disappear. Knock on wood anyways. I will continue the Naltrexone as I believe it in conducive to a healthy immune response.