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Fighting Stress with Adenosine Antagonists.

Ema

Senior Member
Messages
4,729
Location
Midwest USA
And go figure, thanks to @Valentijn, I now know that I have a very rare mutation of these receptors! I wish there was more research on them...

When I am stressed (and I’m stressed a lot of the time, as I bet a lot of you are as well), I turn to coffee. Not just to keep me going through the time when I need to get things done, but also for relaxation. For me, the smell and taste of coffee brings me thoughts of relaxing conversations with friends and other fun times.

But what if the memories weren’t all the relaxing the caffeine was doing for me? What if the chronic caffeine consumption was keeping my stressful life at bay?

It’s time to look at adenosine 2A receptors in the hippocampus. Don’t worry, the coffee will be back.


(Source)

Batalha, et al. “Adenosine A2A receptor blockade reverts hippocampal
stress-induced deficits and restores corticosterone circadian oscillation” Molecular Psychiatry, 2012.


First let’s talk about stress. Specifically, childhood stress. In small doses, stress exposure can actually be good for you, but in large, or prolonged, doses, it’s definitely not. There are effects immediately after stress, as well as long term ones. when you suffer strong stressors in development, you can end up with changes all the way into adulthood, from cognitive deficits to predisposition to psychiatric disorders.

Why is stress in development so important? During development, our brains are developing too, particularly our hippocampus. While the hippocampus is best known for its role in memory and spatial navigation, it’s also extremely important in emotional responses. Neuronal growth in the hippocampus can come from enriched environments or chronic antidepressants, and death of those neurons can come from chronic stress. Chronic stress also disrupts the hypothalamic-pituitary-adrenal axis(the HPA axis) And that’s just in adults! During development, animals are very susceptible to stress, and the hippocampus is still developing its connections. And we’re still figuring out what changes occur during early life stress and how they relate to behaviors in adulthood.

In this case, the authors of this study were looking at adenosine 2A receptors. Adenosine is a neurotransmitter, a chemical messenger between neurons, that plays a role in promoting sleep as one of its functions. But the role of adenosine really relies on what receptors it hits, and where those receptors are. In the hippocampus, for example, adenosine 2A receptors can increase transmission of glutamate, another neurotransmitter, and can contribute to disorders and dysfunction. For example, high adenosine 2A receptors can be seen in response to acute stress, or in Alzheimer’s. If adenosine 2A receptors in the hippocampus are altered in acute stress, and the hippocampus is altered by chronic stress in early life, does this mean that adenosine 2A receptors could have anything to do with chronic stress?

continued at http://blogs.scientificamerican.com...0/fighting-stress-with-adenosine-antagonists/
 
Messages
15,786
Here's a nice excel spreedsheet of the ADORA receptor SNPs, in 11 ME/CFS patients and 11 controls. Red boxes indicate a genotype present in 1 - 2.5% of the general population, orange is 2.5 - 5%, and yellow in 5 - 10%. SNPs for which there is no variation, or for which all variations are common, or which are duplicates of other SNPs have been excluded.

ADORA.gif


There's not much difference for patients versus controls in ADORA2A, ADORA2B, or ADORA3. However there's a pretty striking difference for ADORA1. On that gene, ME/CFS patients have 5 SNPs in the 2.5 - 5% (orange) prevalence range versus 0 for the controls, and ME/CFS patients have 7 SNPs in the 5 - 10% (yellow) range versus 1 for the controls.
 

Aileen

Senior Member
Messages
615
Location
Canada
@Valentijn I wasn't able to get your rare allele program to work on my computer but I did give you some SNPs. Is my data included in the above table or do you need me to give it to you?
 
Messages
15,786
@Valentijn I wasn't able to get your rare allele program to work on my computer but I did give you some SNPs. Is my data included in the above table or do you need me to give it to you?
It looks like I just have a small set from you, probably for a single gene. If you're willing to send me your entire 23andMe file, I can add it to our ME/CFS patient spreadsheet. I'll contact you with info on how to do it. It also looks like you had the Mac issues with the rare gene analysis program, so I can run that for you while I'm at it.
 
Messages
15,786
Wasn't my rare mutation in another protein that impacted ADORA2A though and not in the ADORA2A itself?
Yours was rs17595410 on USP4. USP4 deubiquinates ADORA2A, which increases the amount of functional ADORA2A receptor on the cell surface. So a problem with USP4 might result in a reduction of ADORA2A receptors.
 
Messages
15,786
Here's a bigger and messier Excel spreadsheet of the ADCY1 - ADCY10 genes, which create the adenylate cyclases. I'm not really sure what it does, except that it messes with adenosine somehow :nerd:

ADCY_full.gif


Basically the rare SNPs are weighted based on how rare they are, and then totaled to see if we're more or less rare than the controls. Overall we're about twice as rare, with the biggest differences seen in ADCY3 and ADCY5, where we're about 5 times as rare :alien: ADCY2, ADCY6, and ADCY8 showed little or no difference.

There were only a couple known missense mutations, and little research regarding up- or down-regulation, though ADCY5 contains a few rare SNPs in the ME/CFS patients which are known to be protective against developing diabetes and a higher birthweight. It's possible that the SNPs which are beneficial in one context are a vulnerability in another context.
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
Ema have u tried modafinil. I have been getting good effects using very low doses like 25mg. Normal dose is 100 to 200mg. I find it improves cognitive energy but not buzzing around over stimulated. I thought its main action was working with dopamine and noradrenaline but have read it works on adenosine as well as the above.
 
Messages
15,786
Here's a few more adenosine-related genes, ADCYAP1, ADA, and ADK:

ADCYAP1-ADA.gif



ADK.gif


So pretty normal for ADCYAP1 and ADA (much more so than the controls), but ADK is looking a bit wonky for several of us. ADK is adenosine kinase, which converts adenosine into AMP and ADP.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
For the first time, the controls and the patients look reversed in the ADA table.

Do you have anything for AMPD1?
 
Messages
15,786
For the first time, the controls and the patients look reversed in the ADA table.

Do you have anything for AMPD1?
One possibility is that some SNPs are protective, or at least advantageous in certain situations. But that could just as easily apply to our own rare SNPs :p

Somehow I missed AMPD1, though I have a big list I'm going through:
ADSS
ADSSL1
ADSL

AK1
AHCY
APRT
AMPD1

GUK1
UBC
USP4

PRPS1
PPAT
PFAS

GART (E1, E2, E3)
PAICS (E1, E2)
ADSLATIC (E1, E2)

IMPDH1
IMPDH2

GMP synthase
GMPR
GMPR2

PNP - Purine_nucleoside_phosphorylase
XDH
HPRT1

Anything else involving adenosine I might be missing?
 
Messages
15,786
Here's ADSS, ADSSL1, AMPD1, AMPD2, and AMPD3. ADSL didn't have any interesting SNPs for us or the controls.

ADSS-AMPD.gif


So not much going on with ADSS, ADSSL1, or AMPD2.

But AMPD1 is quite interesting - rs17602729, which is heterozygous in 4 patients and 0 controls, is a known pathogenic missense mutation. When homozygous or compound heterozygous, it causes muscle pain and weakness due to myoadenylate deaminase deficiency, starting in early childhood. http://omim.org/entry/102770#0001 has some more data. It's possible that being heterozygous is causing a milder and/or later-onset version, or has created a vulnerability which some other factor (such as an infection or immune reaction) has exploited or exacerbated.

AMPD3 is also somewhat interesting. Mutations can result in an absence of adenylate deaminase in blood cells, but it isn't known to cause any illness thus far. But again, it might be interacting with an external factor to cause problems. Even heterozygous mutations in that gene can result in reduced adenylate deaminase levels.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
Yes, yes, yes! That's my theory too an AMPD1...it is slow and thus adenosine builds up and eventually induces hibernation syndrome and then takes out the immune system as well.

Adenosine is antiinflammatory except in excess when it seems to do the opposite.

I know not everyone had high adenosine on the methylation panel but it was common enough that RichvanK took note. And people have been studying the problems in purine metabolism for ages in ME/CFS.

Great work on all this, @Valentijn. It's very interesting to see it all laid out in color like this.
 
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15,786
Here's AK1 - AK5 and CMPK1 and CMPK2. Nothing too interesting, compared to the controls.

AK-CMPK.gif


AK is adenylate kinase, which converts ADP from and into ATP + AMP. CMPK participates in converting ATP into ADP.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
It's possible that the SNPs which are beneficial in one context are a vulnerability in another context.

This is very often the case. The classic case is sickle cell anemia, which can confer immunity to malaria, but its also the case with detox genes. Some people in the population are always more vulnerable to some chemicals, and others more resistant. Its a genetic advantage to the population, though not always to the individual.
 

wastwater

Senior Member
Messages
1,271
Location
uk
On Malacards gene site I saw a mention of RGS2 that acts on PRKG1 and ADCY5 in relation to my rare genetic disorder.And this http://www.uniprot.org/uniprot/P41220
RGS2 links to anxiety Alzheimer's brucellosis T cell activation B cells and IL-2
 
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