In my first blog post, Cracking COVID19: the PLA2 clues, I highlighted Phospholipase A2, and its importance to how SARS-CoV-2 replicates.
In my second post, Magnesemia key to Hypokalemia, COVID-19 damage?, I explore why regular reports of Hypokalemia (potassium deficiency) in COVID-19 patients may be due to an underlying, undiagnosed Hypomagnesemia (magnesium deficiency.)
In this post, I discuss the role of ion channel TRPM6 in Magnesium homeostasis, and I speculate how my first post (Phospholipase A2) and my second post (Hypomagnesemia) interlock.
The pandemic virus, SARS-CoV-2, needs raw materials from which to manufacture copies of itself. It has to take those resources from our bodies.
Among the tools that the virus uses to extract resources from our bodies:
a pair of scissors (phospholipase) to cut up our phospholipids, and
a pair of scissors (exoribonuclease) to cut up our RNA.
We'll look at phospholipase first, but it will lead us right to exoribonuclease.
I have not yet found research indicating how the virus boosts levels of phospholipase, but levels of phospholipase do rise when the virus attacks, and the virus gets supplies when phospholipase cuts our phospholipids.
One of our phospholipids (phosphatidylinositol 4,5-bisphosphate) keeps our TRPM6 ion channels open to magnesium. As the paper says it, "Phosphatidylinositol 4,5-bisphosphate Controls Magnesium Gatekeeper TRPM6 Activity."
Furthermore, the paper finishes with "Our data indicate that PIP2 is required for TRPM6 channel function; hydrolysis of PIP2 by PLC-coupled hormones/agonists may constitute an important pathway for TRPM6 gating, and perhaps Mg2+ homeostasis." Those researchers build upon previous findings re TRPM6 and Mg, including
"that TRPM6 comprises all or part of the apical Mg2+ channel of Mg2+-absorbing epithelia."
Therefore when the virus is replicating rapidly,
and phospholipase is rapidly cutting up phospholipids,
it snips a fatty acid chain off phosphatidylinositol 4,5-bisphosphate (thankfully also known as PIP2), and
TRPM6 ion channel is no longer open to Magnesium.
My analogy is that PIP2 is like a strap keeping open the door (TRPM6 ion channel) so that magnesium can get through. The virus boosts the number of phospholipid scissors, but some of those scissors cut the door strap, the door closes, and magnesium levels drop.
How does that drop in Mg supply matter to the virus? The virus is getting other materials by using that other pair of scissors--exoribonuclease, which cuts off parts of our RNA. Activation of the virus's exonuclease "scissors" requires magnesium. After our TRPM6 door shuts, the magnesium supply drops, and I infer that the exonuclease scissors quit cutting our RNA. I speculate that, at that point, the virus is not getting enough materials to replicate, so within the body the infection rate slows or halts.
If indeed this is how it works, it is a cool little protective trick! It's as if Little Red Riding Hood ties her front door open with a strip of bacon. She enjoys the breeze, but if a hungry wolf happens along, it will snack on the bacon before it proceeds into the house for the main course. Gnaw entrée --> no entry. The door has a spring to pull it closed, so the wolf severs the bacon and the door closes. No more airflow until the wolf goes away. Except that instead of airflow, what we're really talking about is the flow of magnesium.
Unfortunately our bodies need magnesium for many of our most critical processes. It is clear that by starving an infection of magnesium, our biology is severely impacted.
Example 1: Mg 2+-Dependent DNA Synthesis and RNA Degradation
Example 2: Short-term Magnesium Deficiency Downregulates Telomerase, Upregulates Neutral Sphingomyelinase and Induces Oxidative DNA Damage in Cardiovascular Tissues
Example 3: Aging and Magnesium
(which mentions "Ca/Mg high ratio prompts blood coagulation.")
That third example would be triggered by low Mg, which sounds relevant, because hypercoagulation has been reported in COVID-19 patients, and separately, COVID-19 patients regularly are hypokalemic, and hypokalemia can be caused by a magnesium deficiency.
Additionally per hypercoagulation, on April 12, I noted research pointing to adrenaline and 5HT as contributors to platelet thrombi growth. Though not reported in that paper, magnesium is relevant because adrenaline release is attenuated by magnesium.
That last link is worth a read--it is full of relevance, some of which I'll repeat here for your convenient reading:
A Mg deficiency occurs often in ICU patients, in alcoholics and during use of diuretics. Simultaneous administration of Mg is often required for treatment of potassium deficiency. Mg has an anti-arrhythmic effect towards digoxin-mediated dysrhythmias and torsades de pointes, and can be efficient in other arrhythmias. Systematic use of Mg seems to decrease mortality of acute myocardial infarction and is justified during cardiac surgery, often associated with hypomagnesemia, because of vasodilation of coronary arteries and in order to prevent occurrence of arrhythmias. Mg, because of its calcium channel blocking properties and as it lowers the release of epinephrine, is indicated for surgery of pheochromocytoma.
In that passage, you see medical problems that likewise are reported from the ICU for COVID-19 patients. That gives me additional confidence in asserting that magnesium depletion or deficiency is key to the damage done by COVID-19.
Can magnesium availability explain why the virus does not affect children and women as severely as men? That begs for additional research into how
estrogen and estrogen receptors (and repressors), and
growth factors and their receptors
affect TRPM6 expression and function.
From this latter paper,
" stimulation of the EGF receptor (EGFR) leads to an intracellular cascade involving Rac1 that promotes trafficking of TRPM6 to the plasma membrane. Furthermore, long-term EGF treatment upregulates the expression of TRPM6.
"Estrogen has also been shown to stimulate TRPM6 activity upon short-term treatment, next to its long-term regulatory effect on TRPM6 transcription. "
It is important to consider that TRPM6 is not expressed in all parts of the body in the same way. Relationship Between Low Magnesium Status and TRPM6 Expression in the Kidney and Large Intestine.
I searched for but did not find a thorough discussion of TRPM6 in the lungs. I wonder if a virus that cleaves PIP2 in the throat lining and airways would shut not only TRPM6 in the throat and airways, but also signal the magnesium-regulating TRPM6 channels in the kidneys, GI tract, and elsewhere. I have long thought of the lungs as our early warning system, alerting the rest of the body when a pathogen arrives on a breath and trips a detector in the airway lining. I would bet a Dr. Pepper that when the lung TRPM6 channels stop conducting magnesium, TRPM6 and TRPM7 elsewhere in the body detect that change in status and likewise adjust the flow of magnesium to prevent a runaway infection.
Sepsis and hypomagnesemia certainly are related..
While we are exploring relevant mechanisms in the lungs, I predict there will be some welcome breakthroughs in cystic fibrosis research if scientists find a coordination between TRPM6 channels in the lungs and TRPM6 in other parts of the body. In PubMed,
Hypomagnesemia fibrosis returns 62 results
but for
TRPM6 fibrosis I see only 10 results
If they are finding relationships between TRPM6 and hypomagnesemia,
and they are finding relationships between hypomagnesemia and fibrosis,
then presumably there are discoveries to be made studying TRPM6 and cystic fibrosis.
Today my search inPubMed
Found 1 result for trpm6 "cystic fibrosis"
and it was because this paper
contained these separate mentions
"Various members of the TRP superfamily, including
TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers"
"CFTR is a tumor suppressor in several GI cancers.
Cystic fibrosis patients are at a significant risk for CRC"
On this day, April 23, 2020, there was none but this one result. I predict that will change.
For the conclusion of this post, I had intended to finish with a final look at the relationships between
Phosphatidylinositol 4,5-bisphosphate (the phospholipid strap holding TRPM6 open), and
Phospholipase a2 (the scissors that cut phospholipids).
or, more succinctly, PIP2 and PLA2.
I searched for those terms and Endothelin-1, because I had come across the papers
Sputum and Plasma endothelin-1 Levels in Exacerbations of Chronic Obstructive Pulmonary Disease.
There is much more yet to be read, e.g.
I see that PIP2, PLA2, and Endothelin-1 are worthy of an entire article.
For tonight, though, I am through.
Phospholipase A2 and
Hypomagnesemia.
Hopefully, this assembled information sheds more light on COVID-19. If we expect to end this pandemic, we will have to understand the causes of the disease. To the best of my ability, I have tried to contribute to this understanding.
All the best,
John
No comments:
Post a Comment