T3 intracellular calcium and caffeine

[Inara]

Yes, the sigma receptor 1 is an interesting player that is looked upon in research of diseases (like ALS).

I have copied a section of my summary about it (without the references - if there is interest in the references, let me know) - which focuses on IP3R3, but it might still be informative:

The sigma-1 receptor is a transmembrane protein that interacts with ion channels at the plasma membrane and with IP3R3 on the MAM [Mitochondria Associated Membrane], where it exerts a chaperone activity and its function as a Ca2+ sensor. By doing so, it plays an important role in maintaining intracellular Ca2+ homeostasis in both physiological and pathophysiological conditions [15, 81]. Sigma-1 receptors associate with the chaperone BiP/GRP78. Under low ER calcium or upon the binding of agonists, they bind to IP3R3 and prevent ubiquitin-mediated degradation of this calcium channel, which leads to a boost of calcium transfer from the ER to mitochondria. The promyelocytic leukemia (PML) tumor suppressor protein associates with IP3R3 at the MAM which results in an increased opening of the IP3R3 and opposes the activity of the kinase Akt. The interaction of PML with IP3R3 leads to
its hyper-phosphorylation, which results in reduced ERmitochondria calcium flux and apoptosis resistance. The activity of IP3R is regulated by chaperoning through the activity of Sigma receptors and GRP75 (also known as HSPA9) [15].

Sig1R defciency induces dissociation of the MAM components and deregulation of Ca2+ homeostasis at the MAM through mislocalization of IP3R3, resulting in calpain activation, mitochondrial dysfunction, decreased ATP production and neurodegeneration. Sig1R is widely expressed in the CNS, whereas IP3R3 expression is found in the spinal cord and brainstem regions containing motor neurons such as the anterior horn of the spinal cord, the hypoglossal nucleus, and the motor nuclei of the facial and trigeminal nerves. IP3R3 is less expressed in hippocampus, cerebral cortex, or cerebellum. The disruption of the Sig1RIP3R3 interaction is involved in selective degeneration of motor neurons. The co-localization of Sig1R and IP3R3 in adult motor neurons [...] and the predominant localization of IP3R3 at the MAM suggest that IP3R3 is likely to be the key subtype responsible for selective vulnerability of motor neurons in ALS. Moreover, we revealed that mislocalization of IP3R3 from the MAM induced calpain activation and mitochondrial dysfunction [36]. A reduction in Ca2+ flux into the mitochondria leads to lower ATP content in neuronal cells. The authors in [36] conclude that IP3R3-mediated excess cytoplasmic release of Ca2+ may be an initiation step in motor neuron degeneration via calpain and that the deregulation of Ca2+ homeostasis via IP3R3 is one of the key mechanisms for motor neuron degeneration [36].

IP3R(3) plays a role in steroid and hormone production in the sense that it's at the beginning in a chain of steps (production of PLCgamma which leads to formation of DAG and IP3, and IP3 - together with Ca2+ - binds on IP3Rs, and this "initial" calcium signal gives the inition of other reactions that will lead, in the end, to hormones and steroids and much more - see Kegg Online for instance, that's great).

 

[pattismith]

This reminds me - there are lidocain patches. They are usually used for neuropathic pain following varicella zoster infection, but also for other neuropathic pain. I find them very helpful, and you don't have the usual side effects.

Ambroxol patches are believed to be more even more efficient, according to the papers I read.

This looks like another promising way to hack into calcium modulation since there are quite a few ligands already out there for this receptor:

The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum(ER) that modulates calcium signaling through the IP3 receptor.

Interestingly, pregnenolone, progesterone and DHEA are all ligands for this receptor @drob31

@BadBadBear @pattismith @Inara

Very interesting, as we have obvious hormonal balance problem/and or hormonal tolerance problems.

I am low for progesterone but can't tolerate any. Pregnenolone supplementation didn't change any thing, but I didn't try yet DHEA.

 

[Inara]

Ambroxol patches are believed to be more even more efficient, according to the papers I read.

Can you link to the patches?

 

[pattismith]

Can you link to the patches?

sorry, it was tested as a cream, not patch!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701773/


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[Iritu1021]

That's a great summary @Inara - thank you!

@pattismith Last night I was reading a seemingly endless online chapter about sigma-1 and it was almost eerie how it was sort of a potential "unifying theory" for everything else we've talked about: calcium, K and Ca channels, TAAR receptor (back to T1AM), regulation of most steroid hormones and virtually every neurotransmitter in the body, mitochondria, IP3, endoplasmic calcium storage... it's described as an "intracellular signal amplifier" which could explain why people with CFS are so supersensitive to everything. It really, really fits the bill.

It's a very new receptor, just like TAAR, so it's very likely that there's a connection but nobody discovered it yet.

But here's a very important caveat: all the substances acting on this receptor have a bell shaped curve. Which means the effect at very low doses will be an agonist effect and the effect of higher doses is antagonist effect. So if you tried a regular dose of pregnenalone, you might still want to try a micro-dose of it and see if it has a completely different effect. This is how it works for me with micro-dosing T3 - it produced a totally different effect than taking even the lowest normal dose.

Microdosing psychedelics (psilocybin, LSD) is "the next big thing" right now in Silicon Valley, and at microdoses of these drugs act as cognitive and mood enhancers without any hallucinogenic properties. This has been generally attributed to 5HT2A stimulation but they also sigma 1 agonists so that could explain the difference in response as well.

I'm going to play around with my sigma receptors - this all sounds very promising and makes a lot of sense... this subject probably deserves a new thread of its own

 

[junkcrap50]

I am low for progesterone but can't tolerate any. Pregnenolone supplementation didn't change any thing, but I didn't try yet DHEA.

Have you tried transdermal progesterone cream? It seems to be much better tolerated via this delivery method.

 

[Learner1]

Pregnenolone goes straight to unwanted estradiol in me, not to any other hormone. DHEA is helpful.

 

[bertiedog]

DHEA is helpful.

What dose of DHEA do you take and in what form if you wouldn't mind letting me know. Yesterday I got the results of my 24 hour Complete Hormone Panel through Genova and found that I have zero DHEA or testosterone. The so called bad oestrogen was a bit higher than I would like but it was methylated to a not detected level but I do want to look into how this might form high quinolinic acid which showed up at a raised level in the G I effect Genova's test I did a couple of year's ago. Also I had raised kyreunine at that time.

I am hoping that if I take DHEA it will give me a little testosterone and maybe balance out the 4 OH a bit plus help my poor stamina and immune system issues.

BTW I am a carrier for the congenital adrenal hyperplasia gene and I think this is the reason my progesterone always looks good and yet I haven't taken any since 2000 buy have used 0.75 mcg Estrogel since then. Whenever I tried adding any natural progesterone I couldn't tolerate it and could have ended up murdering anyone who upset me!!

All the other oestrogen markers were good just the 4 OH was towards the top of the green range and the MD from Genova said it was the "ugly" oestrogen but the fact that I methylated so well (this was news to me as I always thought my methylation was rubbish) meant it was unlikely to cause cancers which I was particularly concerned about as both my mother had ovarian cancer and died from it and my bother has prostate cancer. We have the bad SNPs CYP1B1 which speeds up Phase 1 Detoxification but homozygous for COMT which slows down the ability of the body to get rid of the oestrogen plus other nasty toxins. Not a good combination at all. (I am so pleased I did the day long webinar on this topic and then followed up by having this test which I can order because I have practitioner status due to my diploma in nutrition).

Pam

 

[Learner1]

Hi Pam,

I take 10mg oral DHEA in capsules, usually from Douglas Labs. Good guess at raising testosterone, you'll have to see.

You might find the attached useful. I am not so sure your methylation is doing what you need it to given what its saying... and as a survivor of uterine/ovarian cancer, I think you are wise to follow up with this, especially since progesterone is problematic.

 

[yurybx]

@Learner1, please tell me how quickly the therapeutic effect appears after the start of DHEA? How did you feel when you started taking this medicine? What improvements did you feel?

 

[Learner1]

DHEA doesn't produce an instant hit, like T3 or hydrocortisone do.

Testosterone and DHEA work more gradually over time, making me feel stronger, more vibrant, helping me build muscle (or at least, not lose it), and be more active.

 

[Remi]

My brainfog has a feeling this thread is of interest to me.

I am hypothyroid, but had issues when subclinical and maybe before that. Levo did nothing and my FT3 did not rise above 45% of the range before overstimulation. Now on NDT my FT3 was above range at 3.25 grain, but still no overstimulation on 4.5 grain. I tested cortisol in saliva to see if I was pooling, but it was OKish. 73% of the range rather than top of range. But not low.

Should I still test sex hormones? I quit Yasmin 6 months ago and am 48 premenopausal. And should I take caffeine once on optimal dose? I avoid it usually. My stomach ache has gone, that I had since being subclinical. So I could take it if way before bedtime.

 

[Learner1]

I am hypothyroid, but had issues when subclinical and maybe before that. Levo did nothing and my FT3 did not rise above 45% of the range before overstimulation. Now on NDT my FT3 was above range at 3.25 grain, but still no overstimulation on 4.5 grain. I tested cortisol in saliva to see if I was pooling, but it was OKish. 73% of the range rather than top of range. But not low.

Have you tested serum ferritin, folate, B12 (preferably methylmalonic acid, not serum B12), selenium, iodine, and rT3? They might give clues as to why thyroid hormones aren't as effective as they could be.

Should I still test sex hormones? I quit Yasmin 6 months ago and am 48 premenopausal.

Being 48 and premenopausal is an excellent time to be testing hormones. I learned this the hard way when my cancerous ovary ruptured at age 52 after being estrogen dominant (due to lack of progesterone) for a few years.... the cancer was also 2/3 of the way through my uterine wall, having quietly and slowly grown over a few years.

Beyond fractionated estrogens and progesterone, testing pregnenolone, DHEA, testosterone, cortisol, ACTH, and SHBG can also be useful, especially for ME/CFS patients.

And should I take caffeine once on optimal dose? I avoid it usually. My stomach ache has gone, that I had since being subclinical. So I could take it if way before bedtime.

Caffeine can be helpful for some people. Its a crutch, but it can help brain for and functioning, and there are other benefits to drinking coffee or tea.

 

[Remi]

Have you tested serum ferritin, folate, B12 (preferably methylmalonic acid, not serum B12), selenium, iodine, and rT3? They might give clues as to why thyroid hormones aren't as effective as they could be.

Yes to ferritin, got it to 95 and am still adjusting iron supp and retesting. Did the Pat Kornic protocol for a year, folate good, homocysteine good, MMA OK, selenium suppleting but not yet tested. Iodine and rt3 not yet tested. These are expensive and I am still retesting homocysteine and b6 to make sure my b12d was from meds I used and low stomach acid, not structural.

Being 48 and premenopausal is an excellent time to be testing hormones. I learned this the hard way when my cancerous ovary ruptured at age 52 after being estrogen dominant (due to lack of progesterone) for a few years.... the cancer was also 2/3 of the way through my uterine wall, having quietly and slowly grown over a few years.

Beyond fractionated estrogens and progesterone, testing pregnenolone, DHEA, testosterone, cortisol, ACTH, and SHBG can also be useful, especially for ME/CFS patients.

Caffeine can be helpful for some people. Its a crutch, but it can help brain for and functioning, and there are other benefits to drinking coffee or tea.

I'm really sorry you went through that and I hope you have healed well from it.

To test all these I'd have to ask my GP who doesn't know about my NDT. Or get money for private testing from somewhere. I'm still in the androgen rebound from quitting Yasmin (acne outbreaks) but this should subside. I don't have any symptoms from perimenopause yet.