GAD1 & 2 glutamate- GABA-balance

[Hope78]

Hi!

A few days ago I got my 23andme reports back.

I am especially interested in the enzyme that is converting glutamine/glutamate into GABA.

The only drugs I ever responded to in a positive way (no more anxiety, less pain, no insomnia) were gaba-ergic drugs like antiepileptics and benzodiazepines. I became very senstive to every medication, so that's no option any longer beside the fact that I don't want to be dependend on benzos. I also do NOT respond positively to the GABA supplement (capsules).

So my doctor suggested to give l-glutamine a try but his concern is about stimulating the NMDA-receptors rather than converting it into GABA via the GAD-enzyme.

I have 9 versions of the GAD1 enzyme, unfortunately promethase is not telling me weather it's the normal or the slow version of the enzyme. I have 3 homozygous versions, two of it rare and hetero versions.

So it's


rs2241165(G;G) (Frequency 2,7%)
1 rs3749034(T;T) (2,7%)
2 rs3828275(G;G)
3 rs2058725(A;G)
4 rs3791851(A;G)
5 rs769407(C;G)
6 rs3791878(C;C)
7 rs12185692(C;C)
8 rs3791850(A;G)

Most oft them are tagged with anxiety disorder & depression.

Does anyone know about it?

I am also homoc. for MAO-A and hetero for COMT, so I guess that could be the reason why normal antidepressants did noting for me instead (some of them actually worsened my condition)

Thank you!

 

[Valentijn]

I have 9 versions of the GAD1 enzyme, unfortunately promethase is not telling me weather it's the normal or the slow version of the enzyme. I have 3 homozygous versions, two of it rare and hetero versions.

Almost all of those are extremely common, and none are missense mutations. Even one of the ones labeled as being rare is only a bit rare in Europeans, and very common in other populations.

I don't think there's anything particularly meaningful in there. If those SNPs cause anxiety, then half the world has anxiety

 

[Hope78]

my doctor was concerned to give me l-glutamate because of that. So you say I can take l-glutamate and it will probably turn into GABA and not only glutamate? That would be great!

Thank you für replying!

PS: So are there known reasons for low GABA when genetics are not the "culprit"? I am also too low in taurine and I read somewhere it assists the GAD in turnin glutamate into GABA. It's all so complex, as a layperson in biochemestry and genetics I am fairly overwhelmed and can only guess what's going on

 

[Valentijn]

my doctor was concerned to give me l-glutamate because of that. So you say I can take l-glutamate and it will probably turn into GABA and not only glutamate? That would be great!

No idea, sorry.

 

[Hip]

@Hope78
Instead of thinking in terms of your genes affecting the GABA-glutamate balance, you might want to look at GABA and glutamate from the brain inflammation perspective.

Brain inflammation might be caused for example by a chronic low level viral infection in the brain. Brain inflammation involves microglial activation, and glutamate is produced as a by-product of microglia operation, which will strongly activate the NMDA receptors.

My theory is that brain inflammation may be causing anxiety disorders in many people, via this production of glutamate by the microglia.

I talk about this inflammation-induced anxiety idea in this post.


In terms of anxiety treatment though, the supplements detailed in this thread have proven to be potent:

Completely eliminated my severe anxiety symptoms with three supplements!

 

[Gingergrrl]

Apologies in advance for another stupid question but I am positive for anti GAD65 antibodies and am wondering from this thread if this relates to GAD1 and GAD2? Are there 65 different versions of this enzyme (or more?) Do all of them relate to converting glutamate to GABA? My doctor said that GAD65 relates to diabetes (which I do not have) and am still trying to figure it out since mine was referred to as an auto-antibody vs. an enzyme so I may not even be asking about the same thing!

 

[Deltrus]

P5P is needed for GAD to function.
https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid#Bio-synthesis

Vitamin B2 is needed to convert B6 to P5P.

B2 needs lots of cofactors because it speeds up a ton of different enzymes. Manganese, selenium, magnesium, zinc, b vitamins(thiamine especially) etc are needed. B2 can deplete fairly quickly depending on the person. Might want to supplement both b2 and P5P.


http://lpi.oregonstate.edu/mic/minerals/manganese

In the brain, the manganese-activated enzyme, glutamine synthetase, converts the amino acid glutamate to glutamine. Glutamate is an excitotoxic neurotransmitter and a precursor to an inhibitory neurotransmitter, γ-aminobutyric acid (GABA) (5, 6).

 

[alicec]

I am positive for anti GAD65 antibodies and am wondering from this thread if this relates to GAD1 and GAD2?

The 65 in GAD65 refers to the size of the protein product - 65 kilodaltons.

There are two genes for GAD, GAD1 and 2, producing proteins of 67 kDa and 65 kDa respectively.

So you have an antibody to the product of GAD2. This gene is expressed in the pancreas hence your doctor's reference to diabetes.

 

[Gingergrrl]

The 65 in GAD65 refers to the size of the protein product - 65 kilodaltons.

There are two genes for GAD, GAD1 and 2, producing proteins of 67 kDa and 65 kDa respectively.

So you have an antibody to the product of GAD2. This gene is expressed in the pancreas hence your doctor's reference to diabetes.

@alicec Thank you for explaining this and I had absolutely no clue that there are two genes (GAD 1 & 2) and that GAD65 is the protein produced by GAD2 and that is what I have an auto-antibody to. Apologies to all of the people who have tried to explain this to me in the past.

I am negative on all tests directly and remotely related to diabetes (blood sugar tests, other antibody tests, etc) and we think this antibody relates to my dysautonomia or breathing symptoms in some other way. It can also sometimes relate to Hashimoto's disease which I have.

I am positive for another auto-antibody which has been my focus for the last two months and I really have not learned much about this one (as you can tell!)

 

[JES]

I also respond positively to benzodiazepines. The problem is that we don't really know if GABA is the root problem, and what makes it worse is that almost all GABAergic drugs build up tolerance in long term. It might well be that increasing GABA is just compensating for excessive NMDA activation through the inflammatory model that was mentioned in an earlier post. I get notable improvements to my anxiety with Magnesium Malate, which happens to be an NMDA antagonist, without any of the slight drowsiness side effects I get from taking GABAergic supplements.

 

[Gingergrrl]

I also respond positively to benzodiazepines. The problem is that we don't really know if GABA is the root problem, and what makes it worse is that almost all GABAergic drugs build up tolerance in long term. It might well be that increasing GABA is just compensating for excessive NMDA activation through the inflammatory model that was mentioned in an earlier post. I get notable improvements to my anxiety with Magnesium Malate, which happens to be an NMDA antagonist, without any of the slight drowsiness side effects I get from taking GABAergic supplements.

I also respond positively to benzos and magnesium malate. Does this make sense knowing that I have the anti GAD65 Ab? Could taking "GABA" be helpful for someone with those antibodies? Am asking anyone who knows and not just @JES!

 

[Gingergrrl]

I am reviving this thread and hoping that someone smart out there could tell me if the supplement "GABA" is a calcium channel blocker in its properties?

I know that Gabapentin is a CCB but is GABA itself a CCB? Thank you in advance to anyone who knows! Have tried Googling this but not getting a definitive answer.

 

[Critterina]

Just looking at https://en.wikipedia.org/wiki/Calcium_channel_blocker, they have a list of Ca++ channel blockers, and they do not mention GABA, gamma aminobutyric acid, which is not the same thing as Gabapentin.

WebMD http://www.webmd.com/vitamins-and-supplements/gaba-uses-and-risks does not identify GABA as a Ca++ channel blocker, and I'm sure they would if it is. That would be a big mistake if they didn't.

 

[Gingergrrl]

Thank you so much @Critterina for those links which I am going to read later today when home w/computer.

Am trying to determine if supplementing with GABA could help me b/c of my anti GAD65 antibodies. Have been wondering if taking GABA could assist in the conversion of glutamate to GABA and in turn, improve my breathing?

However, b/c of my other auto Ab (N type voltage gated calcium channel Ab) I cannot take any calcium channel blockers and got confused if GABA had these properties and wanted to confirm before trying this experiment.

Am finding things that help and others that do not help yet often do not know the mechanism or reasons why.

Thanks again!

 

[Critterina]

I can see where you're going with that, @Gingergrrl . I have no idea if that would help, but GABA wouldn't assist in converting glutamate, would it? If the reaction goes to equilibrium (I think it does), then it would slow the conversion of the reactant because you're adding product. But it might help if you have GABA deficiency. You think?

 

[Gingergrrl]

I can see where you're going with that, @Gingergrrl . I have no idea if that would help, but GABA wouldn't assist in converting glutamate, would it? If the reaction goes to equilibrium (I think it does), then it would slow the conversion of the reactant because you're adding product. But it might help if you have GABA deficiency. You think?

@Critterina I honestly do not know if taking GABA could assist in the conversion but I thought maybe since the auto-antibody is attacking the GAD65 receptor (or whatever is the correct term?!) that it might?

When you said "reactant"- which part is that referring to?

I honestly have no idea if I have a GABA deficiency but thought that I might b/c of the antibody attacking the GAD process. So, even if it just brought me up to equilibrium, it might help?

It's another long shot but figured it couldn't hurt (unless it was a CCB, which it doesn't appear to be).

Am still waiting for IVIG approval and tinkering with things on my own until then. I suspect these Abs play a really large role in my illness and minuscule changes in meds/supps have led to some recent improvements and am motivated to try anything I can think of to further improve my breathing/dyspnea and MCAS (my two main issues.)

 

[Critterina]

@Gingergrrl ,

Ah, yes. I'm speaking chemistry. Sorry. It's like cooking: reactants are the ingredients, the products are the cake.

If the reaction can go forward and backwards, it keeps doing that until the products and reactants are in some balance. That's what's called equilibrium. Add reactants, the reaction goes forward, add products, the reaction goes backward, all until the balance is achieved. Same thing if you use up products, more products are made, until the reactants and products are in balance again. Note that cake baking is not an equilibrium reaction- you'll never get the batter back after the cake is baked.

GAD65 appears to be an enzyme. That would be the equivalent of the oven in my simple, cake-baking analogy. It's what makes the reaction go. You have antibodies that attack the enzyme and I would assume make it not work very well. So, from what I understand, you have glutamate (ingredient), you have an enzyme GAD65 (oven) that you want to use to convert the glutamate into GABA (the cake). If you take GABA, you're not making the GAD65 work better; you're buying ready-made cake.

I wish you the best, tinkering on your own. I have three times done that to my detriment! Be careful, please!

 

[Gingergrrl]

@Critterina Wow, thank you for that detailed analogy, which is not at all how I conceived this issue, and it was very helpful!

Am curious if GAD65 is the oven and it is being attacked by antibody, then it cannot possibly work to bake the cake (ending up with the GABA). So it seems like almost a given that I would have too much glutamate and be deficient in GABA unless I am missing something?

So even if taking GABA does not fix the problem, it might correct some deficiencies from the possible lack of GABA? This is just a wild guess on my part.

Once docs rule out diabetes and Stiff Person Syndrome (and I do not have either) then they think this antibody is not significant but I wonder if it really is?

I agree tinkering around can be risky but the worst reactions I've had thus far (in prior years) have been doctor prescribed! I am also at the point of trying risky treatments hoping they will pay off (I don't mean GABA) but other stuff I hope to try in future.

 

[alicec]

Supplementing GABA would simply be bypassing the GAD enzyme and so might be helpful for GABA deficiencies resulting from a defective enzyme.

Be warned however that GABA doesn't cross the blood brain barrier. There is a GABA derivative which does - brand name Kavanace.

Unfortunately GABA receptors are notorious for rapidly downregulating, so you will quickly lose any beneficial effect. Experimentation with intermittent doses could be worth a try.

 

[Gingergrrl]

Be warned however that GABA doesn't cross the blood brain barrier. There is a GABA derivative which does - brand name Kavanace.

@alicec From what I can tell, Kavinace is actually Phenibut vs. GABA and Phenibut is a calcium channel blocker which is what I am trying to avoid. This is what actually led to my initial confusion and is the factor that has stopped me from trying GABA.

If Phenibut/Kavinace are CCB's and they are marketed as GABA, it makes me unclear which other forms of GABA might also be CCB's?

Do you know and also curious if @Critterina might know (b/c from the links you provided it seems that GABA is not a CCB... But now I am having doubts about this again!)