PEMF and voltage gated calcium channels

Normally the inside of the cell is negatively charged relative to the outside. When the membrane depolarizes (the side becomes more positive), the S4 helix moves through the S4 and S5 linkers to the cytoplasmic ends of the S5 and S6 helices. This opens the activation gate which is formed by the inner side of the S6 helices in the α1 subunit. voltage gated Ca²⁺ channels. Magnawave classes suggest muscle twitching during PEMF sessions might be the result of activation of VGCC. MagnaWave also teaches that low and high blood pressure are PEMF contraindications. This post goes with the conventional wisdom that VGCC might be involved with PEMF and presents an entirely different hypothesis as to how.

Martin Pall, 50 Hz PEMF and 5G

Pall ML. Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects. J Cell Mol Med. 2013 Aug;17(8):958-65. PMC free article

1. The Pall review cited 23 studies mostly with 50/60 Hz PEMF and some with static electric and magnetic fields implicating voltage gated calcium channels as a mechanism of action.
2. Voltage-gated calcium channel stimulation leads to increased intracellular Ca²⁺, can bind to calmodulin, which can bind to nitric oxide synthase, which produces nitric oxide. Nitric oxide binds to guanylyl cyclase, which produces cyclic GMP (cGMP) from GTP. cGMP activates protein kinase G which activates myosin light chain phosphatase, which causes vascular smooth muscle to relax. Other therapeutic outcomes may be realized with PKG.
3. The discussion got into the dark side of nitric oxide and reaction with superoxide to form reactive nitrogen species peroxynitrite.
4. This review went into electromagnetic field stimulation of bone growth via the protein kinase G pathway. Pall also got into single-stranded DNA breaks involves a Ca²⁺/elevation/nitric oxide/peroxynitrite/free radical (oxidative stress) pathway.

All of these numbered points are well supported by the peer reviewed literature. Response of the voltage gate to electromagnetic fields is not. There are other moving parts as we will see.

on to 5G, look at all the charges on VGCC then read the quoted text

Dr. Pall’s more recent focus seems to be on 5G and microwave radiation from 5G cell phone towers.

“The forces produced by even weak electronically generated EMFs on each of the 20 positive charges in the VGCC voltage sensor are thought to be very strong for each of three distinct reasons, which act multiplicatively:

1. Electronically generated EMFs are highly coherent, as discussed above, being emitted with a specific frequency, in a specific vector direction, with a specific phase and specific polarity. This high level coherence causes the electrical and magnetic forces produced by these to be vastly higher than are forces produced by incoherent natural EMFs.
2. The forces on these charges in the voltage sensor are thought to be approximately 120 times higher than forces on charges in the aqueous phases of our cells and bodies, due to the dielectric constant of the VGCC charge environment acting via Coulomb’s law (Pall, 2015 & 2018).
3. The forces on the charges in the voltage sensor are also thought, to be approximately 3000 times higher because of the high electrical resistance of the plasma membrane and therefore the high level of amplification of the electrical field across the plasma membrane (Pall, 2015 & 2018). This helps us to understand how VGCCs and other voltage-gated ion channels can be activated by what are considered to be very weak EMFs. One puzzle discussed in (Pall, 2013) and also below in this paper is how can static magnetic fields activate the VGCCs when physics shows that static magnetic fields cannot put forces on static electrical charges.”

The featured image shows a voltage gated Ca²⁺ colored by oxygen (red, tends to have negative charge) and nitrogen (blue, tends to have positive charge). There are so many positive and negative charges on the entire channel that might orientate in electromagnetic fields. The question becomes can they re-orientate?

electromagnetic fields: dielectic heating water, and biomolecules

An electric field is a region of space around an electrically charged particle or object in which an electric charge would feel force. A magnetic field is produced by a moving electric charge. PhysicsKnowledge.com has an interesting take on how microwave ovens work. Like permanent magnets, water molecules have dipole moments, the oxygens being more positive charged than the hydrogens. The friction of them aligning and realigning with the the electromagnetic field creates friction that heats up the water. Water molecules can flop around in the electromagnetic waves. Wikipedia authors have written quite a bit on the history and principles of microwave ovens. Following Wikipedia links, dielectric heating of biological molecules in solution is pretty good too. Radio frequencies are also used for heating by kinetic energy of aligning and realigning molecules with electrical dipoles in the electromagnetic field. No one has ever heard of heating up water with blue light. The frequency is too fast for a water molecule to flop around in this electromagnetic breeze. How fast in Hz does the EMF have to be to have frictional heating due to the flipping around.

Le Blanc C, Mironneau C, Barbot C, Henaff M, Bondeva T, Wetzker R, Macrez N. Regulation of vascular L-type Ca²⁺ channels by phosphatidylinositol 3,4,5-trisphosphate. Circ Res. 2004 Aug 6;95(3):300-7. Sci-Hub free paper

Abstract—Modulation of voltage-gated L-type Ca²⁺ channels by phosphoinositide 3-kinase (PI3K) regulates Ca ²⁺ entry and plays a crucial role in vascular excitation– contraction coupling. Angiotensin II (Ang II) activates Ca ²⁺ entry by stimulating L-type Ca ²⁺ channels through Gα-sensitive PI3K in portal vein myocytes. Moreover, PI3K
and Ca ²⁺entry activation have been reported to be necessary for receptor tyrosine kinase-coupled and G protein-coupled receptor-induced DNA synthesis in vascular cells. We have previously shown that tyrosine kinase-regulated class Ia and G protein-regulated class Ib PI3Ks are able to modulate vascular L-type Ca ²⁺ channels. PI3Ks display 2 enzymatic activities: a lipid-kinase activity leading to the formation of phosphatidyl-inositol 3,4,5-trisphosphate [PI(3,4,5)P₃ or PIP₃ and a serine-kinase activity. Here we show that exogenous PIP₃ applied into the cell through the patch pipette is able to reproduce the Ca ²⁺ channel-stimulating effect of Ang II and PI3Ks. Moreover, the Ang II–induced PI3K-mediated stimulation of Ca ²⁺ channel and the resulting increase in cytosolic Ca ²⁺ concentration are blocked by the anti-PIP₃ antibody. Mutants of PI3K transfected into vascular myocytes also revealed the essential role of the lipid-kinase activity of PI3K in Ang II–induced Ca ²⁺ responses. These results suggest that PIP₃ is necessary and sufficient to activate a Ca ²⁺ influx in vascular myocytes stimulated by Ang II.

This particular Frontiers figure shows morphine receptor coupling to VGCC, The VGCC and PI3K cartoon of this full text article illustrates that VGCC can act to cause contraction or cell proliferation.

VGCC voltage sensor

Let’s go to UniProt.org for a stereotypical VGCC alpha subunit 1F, human just for kicks.

These are some images from Wikipedia and UniProt. It is conceivable that an electrical field sensing, positively charged alpha helix might be able to flop around in a 10 Hz breeze but not in an electromagnetic oscillating breeze a million times faster. Unlike a permanent magnet aligning with the magnetic field of the earth, it is hard to conceptualize how a mostly positively charged movable part is going to perform such an alignment. Only the D (aspartic acid) can be predicted to have a negative charge. Such a positively charged helix might move relative to the rest of a molecule in response to and EMF field. The S4 voltage just does not seem to have a dipole moment.

VGCC and superoxide

Rightly or wrongly, the publications of Martin Pall caste a skeptical light on the extremely low electromagnetic frequencies used in PEMF. We are taught that muscle twitching is due to VGCCn None of the traditional mechanisms of gating really seem to make a lot of sense.

Chaplin NL, Amberg GC. Stimulation of arterial smooth muscle L-type calcium channels by hydrogen peroxide requires protein kinase C. Channels (Austin). 2012 Sep-Oct;6(5):385-9. PMC free paper

“

Changes in intracellular calcium regulate countless biological processes. In arterial smooth muscle, voltage-dependent L-type calcium channels are major conduits for calcium entry with the primary function being determination of arterial diameter. Similarly, changes in intracellular redox status, either discrete controlled changes or global pathological perturbations, are also critical determinants of cell function. We recently reported that in arterial smooth muscle cells, local generation of hydrogen peroxide leads to colocalized calcium entry through L-type calcium channels. Here we extend our investigation into mechanisms linking hydrogen peroxide to calcium influx through L-type calcium channels by focusing on the role of protein kinase C (PKC). Our data indicate that stimulation of L-type calcium channels by hydrogen peroxide requires oxidant-dependent increases in PKC catalytic activity. This effect is independent of classical cofactor-dependent activation of PKC by diacylglycerol. These data provide additional experimental evidence supporting the concept of oxidative stimulation of L-type calcium channels.”

Chaplin NL, Nieves-Cintrón M, Fresquez AM, Navedo MF, Amberg GC. Arterial Smooth Muscle Mitochondria Amplify Hydrogen Peroxide Microdomains Functionally Coupled to L-Type Calcium Channels. Circ Res. 2015 Dec 4;117(12):1013-23. PMC free article

This paper feeds directly into the notion that “therapeutic” PEMF results in the production of small amounts of reactive oxygen species by the mitochondria and/or cry2. This is a direct quotation of the novelty and significance section of the Chaplin 2015 publication.

“What Is Known?

• Angiotensin II (Ang II) is a clinically targeted endogenous vasoconstrictor implicated in the development of cardiovascular diseases including hypertension and congestive heart failure.
• In arterial smooth muscle, Ang II receptor activation promotes localized reactive oxygen species (ROS) generation by NADPH oxidase which is associated with colocalized calcium (Ca²⁺) influx through L-type Ca²⁺ channels.
• Mitochondria are also a source of ROS generation and are known to integrate Ca²⁺ and ROS signaling pathways in many cells.

Note that some think that the super oxide anion O₂^●- generated by NADPH oxidase must go through anion channels in the plasma membrane to react with intracellular proteins.

What New Information Does Chaplin 2015 et al Contribute?

• Mitochondria residing near the plasma membrane of rat cerebral arterial smooth muscle cells are associated with sites of elevated Ca²⁺ influx through L-type Ca²⁺ channels.
• Following Ang II exposure, subplasmalemmal mitochondria amplify localized ROS (hydrogen peroxide) production initiated by NADPH oxidase in signaling microdomains resulting in protein kinase C-dependent activation of neighboring L-type Ca²⁺ channels.
• This mitochondrial ROS-dependent stimulation of L-type Ca²⁺ channels contributes to contraction of rat cerebral arteries by Ang II.
• Disrupting mitochondrial ROS production in vivo normalizes arterial function and attenuates the hypertensive response to pharmacologically-induced systemic endothelial dysfunction.

Mitochondria are a major source of cellular ROS. In addition, mitochondrial dysfunction is associated with cardiovascular disease. However, the importance of mitochondrial ROS in Ang II-dependent arterial contraction and in hypertension-associated arterial dysfunction is unclear. In this study we tested the hypothesis that mitochondrial ROS generation regulates the activity of L-type Ca²⁺ channels in rat cerebral arterial smooth muscle in the context of Ang II signaling. Using an image-based approach, we found that mitochondrial amplification of ROS (hydrogen peroxide) signaling near the plasma membrane stimulates L-type Ca²⁺ channels.”

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So instead of G protein coupled receptors activating PKC that modulates VGCC gating we have ROS activating phospholipse C that makes diacyl glycerol that activates some isoforms of PKC that phosphorylate some isoforms of VGCC. This brings us back to the Martin Pall notion that eNOS is also activated by CaCaM, Ca²⁺, and VGCC.