Possible magneto-mechanical and magneto-thermal mechanisms of ion channel activation in magnetogenetics

Abstract

The palette of tools for perturbation of neural activity is continually expanding. On the forefront of this expansion is magnetogenetics, where ion channels are genetically engineered to be closely coupled to the iron-storage protein ferritin. Initial reports on magnetogenetics have sparked a vigorous debate on the plausibility of physical mechanisms of ion channel activation by means of external magnetic fields. The criticism leveled against magnetogenetics as being physically implausible is based on the specific assumptions about the magnetic spin configurations of iron in ferritin. I consider here a wider range of possible spin configurations of iron in ferritin and the consequences these might have in magnetogenetics. I propose several new magneto-mechanical and magneto-thermal mechanisms of ion channel activation that may clarify some of the mysteries that presently challenge our understanding of the reported biological experiments. Finally, I present some additional puzzles that will require further theoretical and experimental investigation.

Uncovering a possible role of reactive oxygen species in magnetogenetics

“…While several groups have reproduced the key observation that a sufficiently strong magnetic field can gate TRPV1 [15][16][17] and TRPV4 18,42 , some theoretical calculations have questioned whether ferritin's magnetic properties are sufficient to actuate the channels by either localized heating or mechanical force 24 , as has been proposed. Additionally, follow-up studies of the TRPV4-ferritin platform by Wang et al 43 , Xu et al 44 , and Kole et al 45 , all using electrophysiological readouts, have been unsuccessful in recapitulating the results by Wheeler et al 18 , leading others to suggest alternative physical mechanisms that may account for the growing body of empiric data 42,46,47 . However, none of these studies proposed a possible chemical mechanism, a possibility that was tested here using chemical inhibitors or quenchers of reactive oxygen species generation.…”

“…Barbic performed theoretical modeling of ferritin and found that at high iron loading, clusters of iron spins can exist that generate heating above k B T in the presence of a sufficiently strong magnetic field 46 . This led to the suggestion that a second possible mechanism could be considered in which magnetic fields could gate TRPV1 tethered to ferritin through mechanical actuation, either by diamagnetic repulsion of the cell membrane by ferritin or as a result of an Einstein-de Haas effect 46 . In the latter case, a change in the angular momentum of a ferritin nanoparticle in an AMF translates into rotation of the ferritin nanoparticle, which can apply sufficient torque to gate an adjacent TRPV1 channel.…”

“…Additionally, follow-up studies of the TRPV4-ferritin platform by Wang et al . 43 , Xu et al 44 , and Kole et al 45 , all using electrophysiological readouts, have been unsuccessful in recapitulating the results by Wheeler et al 18 , leading others to suggest alternative physical mechanisms that may account for the growing body of empiric data 42 , 46 , 47 . However, none of these studies proposed a possible chemical mechanism, a possibility that was tested here using chemical inhibitors or quenchers of reactive oxygen species generation.…”

Localized nanoscale induction by single domain magnetic particles

“…If noise arising from precession is more important, the system could instead be driven with a microwave frequency electromagnetic field corresponding to the ferromagnetic resonance frequency of the ferritin. If either of these approaches resulted in quantifiable changes in the / threshold required for magnetogentic actuation, it would not be well explained by other proposed mechanisms (Barbic, 2019).…”

“…These studies typically incorporate one or more units of the iron storage protein ferritin into a transient receptor potential vanniloid (TRPV) channel protein. Because the TRPV family is known to trigger calcium influx in response to mechanical and thermal cues, magnetic interactions with ferritin have been presumed to be a source of similar effects (Barbic, 2019). However, cogent critique has cast doubt on these speculated mechanisms (Meister, 2016).…”