PEMF and voltage gated calcium channels

Pulsed electromagnetic frequency therapy enthusiasts and those who are simply dubious of 50Hz and radiofrequency electromagnetic pollution like to point to opening of voltage gated calcium channels as a mechanism. This post is not meant to convince these groups that it doesn’t happen. This post is meant to convince these groups that our natural world is far more complicated than they imagine. This post will focus on the Cav1.1 class L voltage gated Ca²⁺ channel. It is rather interesting because it not only opens in response to a change in membrane potential but also connects to the ryanodine receptor that opens intracellular stores of Ca²⁺. RyR is also a receptor for caffeine. Electromagnetic pollution may influence VGCC indirectly via the mitochondria. The number of literal moving parts of Cav1.1 is a bit bewildering.

Cannel basics

A up and down moving lid, Heiss 2025

There are different types of bottle lids. Does the voltage gate act as a “slide top” or a “push button spout” ? Many times voltage gates are drawn as the flip caps on a condenment bottle.

Heiss 2025 performed a Molecular Dynamics study using the above crystal structure of the voltage gated L-type Ca²⁺ channel . They analyzed the state-transitions of the first voltage sensing domain of Ca_V1.1 exposed to an electric field and site directed mutagenesis of gating- and countercharges to investigate the role of their interactions in determining the gating properties of Ca_V1.1. In silico alanine-substitutions of gating charges differentially altered the kinetics or voltage-dependence of activation, depending on whether they pass the hydrophobic constriction site (HCS) (R2, R3) or not (K0, R1, R4). In this cartoon the lysines (Ks) and arginines (Rs) may be separated by several uncharged amino acids. Alanine-substitutions of countercharges differentially altered kinetics and voltage-dependence, depending on whether they facilitate the transfer of gating charges across the HCS (E100, D126), and whether they stabilize the activated (E87, E90, E140) or the resting state (E100, D126). Their results reveal basic mechanistic principles by which variable interactions between gating charges and countercharges regulate the gating properties of voltage-gated calcium channels. There are other subunits of Cav1.1 in the crystal structure that Heiss 2025. The important one is the purple one. I rendered the same structure according to charge on the NCBI/structure website. There are not that many charged residues in the transmembrane region. The focus was on the first voltage sensing domain because Savailli 2021 demonstrated it to be the most important.

Savalli 2021 connections

This cartoon also appeared in the Muscle Twitching post. It was adapted from the concluding Fig 10 of Savoli. It was quite the journey of fluorescently tagged voltage gates, patching electrical recordings of expressed Cav1.1 channels in frog oocytes, and modeling.

1. Fig 1. Three different currents of Cav1.1 There’s the gating current of the voltage gate opening, the small current through Cav1.1 itself, and the current of the Ca²⁺ evoked Ca²⁺ channel RyR. Note the 10 msec time frame.
2. Fig 2. is a negative control showing that no cyteines that belong in the channel can be labeled with a fluorewcent probe that responds to depolarizations. These authors engineered cysteines so as to attach fluorescent probes to monitor parts moving around. There are no native cysteines that can be labeled with a fluorescent probe that respond to a depolarization. Remember this for our hydrogen peroxide discussion. Fig S1 shows the amino acid sequences of the voltage sensing helices. The funny glowing Y purple thing is where the native hydrophobic amino acid was mutated to a cysteine and then labeled with a fluorecent probe to detect moving arund of the S4 voltage gate
3. Fig 3 Fluorescent probes in action! Cav1.1 is expressed in frog oocyte. The Ba²⁺ currents are recorded with an electrode at the same time fluorescent signals.
4. Fig 4 Voltage gates respond differently to depolrizations.
5. Fig 5 A naturally occurring, charge-neutralizing mutation (R174W) impairs VSD-I activation and voltage-dependent channel opening, leaving VSDs II, III, and IV unaffected. 
6. Fig 6 Scheme of a structurally relevant, allosteric model of Ca_V activation, accounting for both time- and voltage-dependent properties of VSD activation and pore opening. 
7. Fig 7 VSD-I is the main contributor to Ca_V1.1 pore opening.

There were more figures in Heiss 2025 that became very biophysical.

Martin Pall 2013 , 2018 50 Hz PEMF and 5G

In all of his reviews, Martin Pall does an exceptional job reviewing what seems like everything ever written about 50 Hz pollution from the electrical grid to 5GHz from cell phone towers. He gets into some very biophysical considerations on the atomic level. Just taking one channel Cav10.1: Four different gates moving one way, not standing alone but connected, timing is everything…. All of Martin Pall’s reviews fcus on this pathway: Ca²⁺ binds to calmodulin, which binds 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. Nitric oxide may also react with superoxide which produces peroxynitite. Peroxynitrite is a reactive nitrogen species. Some where this electromagnetic polution is generating superoxide that may be dismutated to a lesser evil of hydrogenperoxide.

VGCC and hydrogen peroxide Chaplin 2012

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.

“

“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.”

VGCC and hydrogen peroxide Chaplin 2015

Chaplin 2015 tested the hypothesis from Ang II production of small amounts of reactive oxygen species actiiates protein kinase C in isolated arterial myocytes.

“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.”

.

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.

Summing things up

I chose the featured image after finishing this post. I think it is possible that the things Martin Pall described and physics orientated PEMF fans like to say happen could happen. I think the mechanics are a bit complex and reactive oxygen species mechanisms involving mitochondria need to be examined.

References

• 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
• 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
• Heiss MC, Fernández-Quintero ML, Campiglio M, El Ghaleb Y, Pelizzari S, Loeffler JR, Liedl KR, Tuluc P, Flucher BE. Voltage-sensor gating charge interactions bimodally regulate voltage dependence and kinetics of calcium channel activation. J Gen Physiol. 2025 Sep 1;157(5):e202513769. PMC free paper
• 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
• Pall ML. Wi-Fi is an important threat to human health. Environ Res. 2018 Jul;164:405-416. free paper
• Savalli N, et al. The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation. J Gen Physiol. 2021 Nov 1;153(11):e202112915. PMC free paper