T3 intracellular calcium and caffeine


Senior Member
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).


Senior Member
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.


Breaking Through The Fog
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 :)