Calcium Signaling and G Proteins

Usually the body maintains very low calcium concentrations inside the cell by pumping the calcium out of the cell or into the calcium storage (endoplasmatic reticulum) with ATPases (pumps that require ATP).
When a cell is stimulated (by an incoming calcium current, a neurotransmitter, etc) it can release calcium from the storage, which leads to an exponential increase of calcium concentrations inside the cell. This influences cellular functions, when calcium binds to enzymes, proteins like the calcium-binding protein calmodulin and activates protein kinases.
Afterwards, ATP transports calcium back out of the cell and into the storage and this restores low calcium concentrations inside the cell.
These changes in calcium concentrations influencing cellular activity, are called calcium signaling.

For the body it is important to be able to both release calcium and then restore low calcium concentrations inside the cell again.

There are different mechanisms to release calcium, when a cell is stimulated.
A main one is by activating the inositol triphosphate receptor with inositol triphosphate.
Glucose can form inositol, with NAD+ (active vitamin B3) as a cofactor (1). Inositol is then turned into the phospholipid phosphatidylinositol. The form phosphatidylinositol-4,5-biphosphate (PIP2) is converted to inositol 1,4,5-triphosphate (IP3), which stimulates the inositol triphosphate receptor, by the enzyme phospholipase C.

(Left: normal state of the cell, with low calcium in the cytosol
right: during calcium signaling, high cytosolic calcium
blue= Calcium, PLC= phospholipase C, PIP2= phosphatidylinositol biphosphate, IP3= inositol triphosphate, IP3R= inositol triphosphate receptor)

 

G proteins can trigger calcium release via inositol phosphate receptor, because a subtype of G proteins (Gq) activates phospholipase C (2).  G protein coupled receptors consist of a receptor outside the cell and a bound G protein in the cell. When the receptor is stimulated by a neurotransmitter, hormone, light etc., the G protein exchanges its bound GDP (guanosine diphosphate) with GTP (guanosine triphosphate), and GTP allows the G protein to be free and active in the cell (7).

 

An Important Role of Calcium Signaling

Calcium can increase function of the energy metabolism. Calcium stimulates a few dehydrogenases in the mitochondria, including the pyruvate dehydrogenase and the NAD-isocitrate dehydrogenase, a dehydrogenase in the citric acid cycle (3).
Activation of the inositol triphosphate receptor (IP3R) has the ability to promote ATP production via increased function of the pyruvate dehydrogenase,  the citric acid cycle and the oxidative phosphorylation:

“Recent work has shown that the IP3R at the endoplasmic reticulum provides Ca2+ to mitochondria constitutively, which in turn promotes conversion of pyruvate into acetyl-coA, tricarboxylic acid cycle activity, and production of ATP by the electron transport chain (58). When the IP3R is not activated, energy levels drop, AMP-activated protein kinase (AMPK) is activated, and autophagy is engaged to preserve energy homeostasis and cell survival (58).”(4)

(Autophagy is the survival mode of a cell, where the cell breaks down some of its components to raise energy levels. (5))

On the other hand, calcium can also have an inhibitory effect on energy production, like during calcium-loading, when excess calcium accumulates (6). High calcium levels over an extended amount of time can damage the cell (7). Therefore, it is important for the cell to also successfully restore low-calcium concentrations after calcium release.
Free calcium in the cell is reduced, when ATP transports it out of the cell or into the cell storage (endoplasmatic reticulum), when it is bound to phospholipids in the cell membrane or to proteins like calmodulin.

Phospholipids are synthesized by the body with CTP, which is produced from ribose in the pyrimidine synthesis pathway.

 

Relevance for ME/CFS

Research has found that parts of the energy metabolism are reduced in people with ME/CFS. Pyruvate is converted more to lactate than in healthy controls and the function of the citric acid cycle and consecutive production of ATP in the oxidative phosphorylation are reduced (8).
A study has found indication of too low activity of the pyruvate dehydrogenase in people with ME/CFS (9).
Improving calcium signaling might help stimulate the energy metabolism in ME/CFS.

Neil McGregor presented his findings at Open Medicine Foundation’s Community Symposium, “Molecular Basis of ME/CFS” in August 2017. He found an increased number of SNP’s (single nucleotide polymorphism) in ME/CFS patients in comparison to healthy controls concerning G protein coupled receptors (10). This might indicate problems with the function of G proteins in ME/CFS. Since a subtype of G proteins activates the phospholipase C and that triggers calcium release, a dysfunction of G proteins might impact calcium signaling and the energy metabolism in ME/CFS.

In my opinion, sufficient GTP levels might be relevant for supporting G protein function. For GTP you first need GMP. GMP is produced in the purine synthesis with ribose. The body can convert glucose to ribose in the pentose phosphate pathway.

GMP can be converted to GDP, and then GTP by addition of phosphate groups (Pi). GDP reacts to GTP in a step in the citric acid cycle:
Succinyl-CoA + GDP+Pi -> Succinate + CoA-SH + GTP

The pentose phosphate pathway, the purine synthesis and the conversion to GTP in the citric acid cycle might be important for producing sufficient GTP.

 

Possible Supplements

Some supplements I tolerate well and take daily, might also have some good effects on calcium signaling:

Vitamin B3:
Vitamin B3/ Niacin is needed for NAD+, the cofactor for converting glucose to inositol. Inositol can turn into phosphatidylinositol and inositol triphosphate which can trigger calcium excretion into the cell. Phosphatidylinositol is a phospholipid and phospholipids can bind free calcium in the cytosol.

HydroxoB12:
I think hydroxocobalamin might support GTP levels, because it can be converted to adenosylcobalamin. Adenosylcobalamin helps break down odd-numbered fatty acids into succinyl-CoA, which might increase the reaction of GDP with succinyl-CoA to GTP in the citric acid cycle.

Vitamin B2/riboflavin:
Vitamin D is produced in the Cholesterol biosynthesis, which uses acetyl-CoA, NADPH and ATP and has vitamin B2 (FMN/FAD) as cofactor for some enzymes.
Cofactors for MTHFR (vitamin B2) and MTR/MTRR might be important to keep folate status up and provide enough formyl-THF for purine synthesis. Vitamin B2 is also needed in the pyrimidine synthesis, which produces CTP for phospholipids. Phospholipids bind free calcium, and vitamin B2 might be able to support that.

I’m still looking into other supplements.

 

Conclusion
I think it might be important to support calcium signaling in ME/CFS. Calcium signaling stimulates the mitochondrial energy metabolism. If G protein function is impaired in ME/CFS, this might also impact calcium signaling.
Processes like the inositol phosphate pathway, ribose- and GTP synthesis might be important for calcium signaling.

 

Read a new post with more details on calcium signaling here.

 

References:

  1. https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/enzymes/GetPage.pl?ec_number=5.5.1.4
  2. http://www.genome.jp/kegg-bin/show_pathway?hsa04020
  3. https://www.ncbi.nlm.nih.gov/pubmed/19413950
  4. https://www.sciencedirect.com/topics/neuroscience/inositol-trisphosphate
  5. https://en.wikipedia.org/wiki/Autophagy
  6. https://link.springer.com/article/10.1007/BF00973148
  7. https://en.wikipedia.org/wiki/Apoptosis
  8. https://www.youtube.com/watch?v=sGBXXlQO49g
  9. https://df6sxcketz7bb.cloudfront.net/manuscripts/89000/89376/jci.insight.89376.v2.pdf
  10. https://www.melbournebioanalytics.org/symptommetabolome-directed-genomics-for-mecfs-by-neil-mcgregor-written-transcription/
  11. https://www.ncbi.nlm.nih.gov/pubmed/2596609

https://en.wikipedia.org/wiki/Purine_metabolism#Biosynthesis
https://de.wikibooks.org/wiki/Biochemie_und_Pathobiochemie:_Hexosemonophosphatweg#1._Teil:_Oxidation_und_Decarboxylierung_von_.CE.B1-D-Glucose-6-phosphat_zu_Ribulose-5-phosphat