Activation of Signal-Transduction Mechanisms May Underlie the Therapeutic Effects of an Applied Electric Field

Activation of Signal-Transduction Mechanisms May Underlie the Therapeutic Effects of an Applied Electric Field

J. C. Seegers,1 C. A. Engelbrecht,2 D. H. van Papendorp1

1Departments of Physiology and 2Physics, University of Pretoria, Pretoria, South Africa
Summary Successful treatment of various medical complaints with an applied electric field has been reported over
the years. The identities of the cellular mechanisms that are influenced by this type of treatment and facilitate the
positive effects remain elusive. A study of many in vitro and in vivo reports revealed that the beneficial effects can be
attributed to the activation of membrane proteins, and specifically proteins involved in signal-transduction
mechanisms. Not only may the proteins be affected but it is now well established that enhanced Ca2+ influx, observed
to follow electric stimulation of cells, also contributes to many calcium-dependent cellular processes which can be
linked to the therapeutic effects discussed in this paper. An hypothesis of the physical changes caused by an applied,
relatively small (103 to 104 V m–1 rangan e), electric field with low to moderate frequency (below 150 Hz), is postulated.
© 2001 Harcourt Publishers Ltd

INTRODUCTION
There are numerous reports of positive clinical effects
after exposure to applied electric fields of relatively small
strength (in the 103 to 104 V m–1 range) which are variable
with low to medium frequency (below 150 Hz). Effects
reported include the alleviation of pain, decreased inflammation, wound and bone fracture healing, enhanced
blood circulation as well as various other conditions
(1–4). Most functions in the human body are tightly controlled, and activation of the processes underlying these
functions must take place at the cellular level. The two
most important communication systems in the body,
which affect cellular functions, are the nervous system
and the hormonal system. A crucial point in the discussion undertaken in this paper is that these two systems
act mainly on the membranes of cells. Since so many
macroscopic functions of the body have been reported to
be positively affected by an applied electric field, we
hypothesize that a remarkably wide range of processes
involved in cellular membrane signal transduction mechanisms are decisively affected by an applied electric field
of specific strength and form. Activation of these mechanisms may then cause the observed beneficial effects.
The effects of an applied electric field on cellular controlling mechanisms located in the cell membrane,
reported in the literature, were investigated. Physical
models to explain the efficacy of applied electric fields
were also considered. Because it is difficult to study cellular control in the intact body, many experiments determining the effects of an applied electric field are
performed in vitro. The extent to which the results
obtained in vitro may be extrapolated to the human body
in vivo is not yet totally clear; the physical arguments to
explain the effects observed in vitro are equally compelling to the situation in vivo.
Activation of signal-transduction
mechanisms may underlie the
therapeutic effects of an applied
electric field
J. C. Seegers,1 C. A. Engelbrecht,2 D. H. van Papendorp1
1Departments of Physiology and 2Physics, University of Pretoria, Pretoria, South Africa
Summary Successful treatment of various medical complaints with an applied electric field has been reported over
the years. The identities of the cellular mechanisms that are influenced by this type of treatment and facilitate the
positive effects, remain elusive. A study of many in vitro and in vivo reports revealed that the beneficial effects can be
attributed to the activation of membrane proteins, and specifically proteins involved in signal-transduction
mechanisms. Not only may the proteins be affected but it is now well established that enhanced Ca2+ influx, observed
to follow electric stimulation of cells, also contributes to many calcium-dependent cellular processes which can be
linked to the therapeutic effects discussed in this paper. An hypothesis of the physical changes caused by an applied,
relatively small (103 to 104 V m–1 range), electric field with low to moderate frequency (below 150 Hz), is postulated.
© 2001 Harcourt Publishers Ltd
Received 7 August 2000
Accepted 5 January 2001
Correspondence to: J. C. Seegers DSc, Department of Physiology,
Medical Faculty, University of Pretoria, PO Box 2034, Pretoria, 0001.
E-mail: iseegers@iconico.za
224
Medical Hypotheses (2001) 57(2), 224–230
© 2001 Harcourt Publishers Ltd
doi: 10.1054/mehy.2001.1292, available online at http://www.idealibrary.com on
This study was supported by APS-Technolog
Applied electric field 225
© 2001 Harcourt Publishers Ltd Medical Hypotheses (2001) 57(2), 224–230
PART 1: EFFECTS OF ELECTRICAL
STIMULATION ON PROTEIN FUNCTION IN THE
CELL MEMBRANE
The cell membrane with its phospholipid backbone is
normally impermeable to all compounds carrying a
charge. Ions can move through their specific protein membrane channels only when these channels are
opened by an appropriate first messenger. Ion channels
are voltage- or ligand-dependent. Furthermore, the conformation and function of membrane proteins can be
affected by an applied electric field (5–7). Specifically, it
has been shown that the charge distributions on macromolecules are affected when the electric environment is
changed. As a result, most biological molecules have different accessible conformational states with different
electric properties. It follows that an applied electric field
may affect membrane proteins with various functions,
including enzyme activity (Na+/K+ATPase and
Ca2+ATPases), ion channels, transport systems and receptors, by affecting the charge distribution (i.e. the confirmation) on these molecules.
SPECIFIC MEMBRANE PROTEIN-LINKED
FUNCTIONS AFFECTED BY AN ELECTRIC FIELD
The effects on specific proteins and the cellular functions
connected with these proteins will be discussed.
Ion-channels
There is ample evidence that an applied electric field of
appropriate strength opens Na+-, Na+/K+ and Ca2+-channels (10–13). After opening of the Na+-channels,
enhanced Na+ inflow causes an action potential leading
to depolarization of the cell. Opening of the Ca2+ channels causes an increase of Ca2+ influx which affects
numerous cellular activities at the basis of the optimal
functioning of the body, including cell shape changes,
signal transduction mediation, muscle contraction,
cytoskeletal reorganization (14–19), cell orientation and
migration (14), immune-cell functions (18), cell proliferation (20,21), and metabolic processes (22).
Proteins involved in the activation of other membrane
signalling mechanisms
Noradrenaline release
Application of an external electric field causes the release
of the neurotransmitter noradrenaline (NA) (23,24). The
released NA will further activate many other cellular
processes through the activation of the membrane signaltransduction pathway leading to Ca2+ inflow and the formation of second messengers including cAMP (25).
Numerous metabolic processes are subsequently activated by cAMP-dependent protein kinases through the
phosphorylation of specific proteins by using ATP (25).
Inflow of Ca2+ into the cells, apart from the effects listed
above, will also activate many cellular processes through
the binding to calmodulin, which will then activate
calmodulin-dependent kinases. Increased cellular Ca2+ in
conjunction with diacylglycerate will furthermore activate protein kinase C. The function of all these kinases is
to phosphorylate proteins using ATP. The phosphorylation of intracellular proteins causes conformation
changes. The conformation changes cause the proteins to
perform specific cellular functions in target cells.
Therefore, an exogenous electric field, through its
enhancement of Ca2+ influx, C-AMP production and NA
release respectively, should have a far-reaching effect on
the functions of cells and consequently on the optimal
functioning of the body (13–25). Since no serious side
effects have been reported after electrical treatment using
fields in the range 103 to 104 V m–1 and of low to moderate frequency, it can be assumed that cellular functions
are positively affected.
Growth hormone/factors production and cell growth
For cells to start multiplying as part of wound healing and
tissue regeneration, the appropriate cells must first be
activated by a specific growth factor/hormone, which acts
on receptors on the cell membrane. This activation also
leads to protein phosphorylation using ATP. The phospho-proteins activate the tyrosine-kinases linked to the
control processes involved in cell cycle control and therefore in cell growth. Recently, it was shown that an applied
electric field increases the production and activation of
several growth factors (26–28). The positive effects of
electric therapy on wound healing can in part be
explained by these effects (see Part 2 of this paper).
The following growth factors are affected by an applied
electric field:
Vascular endothelial growth factor (VEGF). Increased
VEGF-mRNA production, translation and secretion after
exposure to an electric field was recently reported by
Kanno et al. (1999) (26). VEGF is necessary for angiogenesis and the authors suggested that electrical treatment
may be beneficial for patients with serious ischemic diseases. They further proposed that this type of treatment,
which is simple as well as practical and is without side
effects, may prove to be of great therapeutic value (26).
IGF-II implicated in bone fracture healing. There are
many reports described in which bone cells exposed to
low frequency pulsed electric fields showed enhanced
proliferation (13). In one report (27), enhanced bone cell
growth was associated with increased IGF-11 (insulin
growth factor-11) mRNA synthesis and subsequently
increased secretion of this growth factor.
Prostaglandin E2 (PGE2) implicated in bone cell healing. Prostaglandin E2 (PGE2) is another growth factor,
apart from Ca2+, VEGF and IGF-II, which is implicated in
electrically stimulated bone cell growth (4). Lorich et al.
1998 (4), found that electric stimulation increased Ca2+-
dependent phospholipase-A2 activity, which caused an
increase in PGE2 which then acted as mitogen in bone
cell proliferation (4).
EGF receptor-accumulation at the cathode-facing pole
after exposure to an electric field. The redistribution of
the receptor of epithelial growth factor (EGF) has been
reported by Guigni et al (1987) (28). This redistribution
enhanced the growth effects of EGF.
It is well established that an applied electric field
causes increases in cell growth, although the controlling
mechanisms were not always identified. Apart from the
effect on the growth factors shown above, which indicate how the control of cell growth is affected, increased
DNA synthesis, mRNA synthesis, optimal cell orientation, and cell differentiation processes associated with
cell growth have been reported after exposure to an
applied electric field. Many observations of increases in
protein and DNA synthesis (20,21,29,30) confirmed
the positive effects of electrical therapy on cell proliferation.
Role of ATP in applied electrical stimulation
All the above listed signal-transduction mechanisms,
which activate various cellular processes, do so through
phosphorylation of target proteins. ATP is necessary for
this activation process. Furthermore, all the ion pumps
use ATP to remove the cations from the cells after influx
through the electrically opened channels. None of the
reportedly stimulated mechanisms could function without attendant stimulation of ATP-production. Indeed,
several reports on the effects of a small applied electric
field on ATP production were found (5,31–33).
The necessity of cytoplasmically generated ATP for
cytosolic Ca2+ homeostasis after exposure to an applied
electric field was also shown (33).
After Ca2+ ions move into the cell the calcium must be
removed fairly quickly from the cytoplasm into the
smooth endoplasmic reticulum, mitochondria, or
pumped across the cell membrane into the interstitial
fluid, in order to retain the calcium balance in the cells. In
all three cases mentioned above, Ca2+ is removed from
the cytoplasm by Ca2+ATPases. These pumps utilize ATP
for the removal of the calcium. Numerous reports of
increases in ATP levels after exposure to an applied electric field have been published (31–33). As discussed
above, ATP is utilized for maintaining Ca2+ levels and for
the phosphorylation of proteins responsible for the final
activation of cellular functions.
The metabolic processes responsible for increased ATP
production during electrical stimulation remain unclear.
The enhanced inflow of Ca2+ may be involved. It is known
that an increased influx of Ca2+ activates the Crabtree
(anaerobic ATP production) effect (34), which enhances
glycolysis in the cytoplasm but inhibits ATP-synthase in
the mitochondria. Therefore, the ATP produced in the cell
under these circumstances would most likely be anaerobic. The decrease in ATP production in the mitochondria
is a result of the increased mitochondrial Ca2+ (35). Since
an applied electric field enhances ATP production, the
observed increases in ATP production due to an applied
electric field may be explained as a result of the electrically stimulated Ca2+ influx activating glycolysis and subsequently anaerobic ATP production. Wojtczak et al.
(1999) (35) showed in detail that Ca2+ influx will inhibit
the mitochondrial F(1)F(0) ATP synthase, and favour the
Crabtree effect in the cytoplasm.
There is also evidence for enhanced glucose uptake
after electric stimulation that may ensure an adequate
glucose supply for the anaerobic production of ATP
(36,37). Electrical stimulation enhanced the levels
of Glut-4 (glucose transporters) in the membranes of
muscle cells and subsequently increased the glucose
uptake in these cells. The increased glycolysis that
followed resulted in increased ATP production. The Glut4 glucose transporters were more affected than Glut-1 in
skeletal muscle exposed to an electric field (36,37).
ATP-release in cells exposed to an electric field
Electric field exposure not only stimulates cytoplasmic
ATP production, it also stimulates the release of ATP from
the stimulated cell. Extra-cellular ATP can function as an
autocrine as well as a paracrine signal which may influence many cellular functions through the activation of
purinergic receptors (38–40).
The release of ATP after exposure to an electric field
indicates a further possible mechanism of enhanced signal transduction. Both ATP and NA were released after
the tissue was electrically stimulated (41).
Conclusion of Part I
From the above data obtained in the literature it is clear
that a relatively small applied electric field affects many
membrane-linked controlling mechanisms, which may
explain the observed therapeutic effects reported as a
result of electric therapy. It furthermore also increases
ATP levels which provide the necessary energy for the
activated cell to perform the necessary cellular processes
underlying optimal body functioning. The next part
discusses the therapeutic effects linked to the protein
functions discussed in Part 1.
226 Seegers et al.
Medical Hypotheses (2001) 57(2), 224–230 © 2001 Harcourt Publishers Ltd
Applied electric field 227
© 2001 Harcourt Publishers Ltd Medical Hypotheses (2001) 57(2), 224–230
PART 2: THERAPEUTIC EFFECTS OF A SMALL
APPLIED ELECTRIC FIELD THAT CAN BE
LINKED TO ENHANCED SIGNAL TRANSDUCTION
A short description of the following healing processes after
treatment with a small applied electric field will be given.
Wound healing and tissue regeneration
Healing in an experimental wound model was ascribed to
increased cell proliferation (29). Wound healing, however,
entails many processes, including: tissue regeneration, new
capillary formation, enhanced local blood flow, and inhibition of microbial growth. As described in Part 1, an applied
small electric field enhances cell proliferation (27–30)
and therefore tissue regeneration. Kanno and co-workers
(1999) also showed that capillary formation may be initiated by an applied electric field (26). There is also evidence
that electric treatment of this nature may enhance local
micro-circulation by increasing the levels of the vasodilater nitrogen oxide (NO) (42–45). These reports show that
an applied electric field enhances NO-synthase activity and
by so doing enhances NO production which has a
vasodilatory effect. This effect of NO may be implicated in
improved micro-circulation. This latter effect may also contribute to the decrease in local edema seen after electric
treatment. The activation of NO synthase is in part regulated by Ca2+ influx (42).
An important factor in activating all of the above, is
amplitude and frequency modulation of cellular metabolic oscillations which contribute to intracellular mitotic
signalling synergy and NO production (46). This issue is
expanded in section 3. The positive effects of electrical
stimulation were discussed above (26–29,42–44).
It has been suggested that the presence of an electric
field enhances wound healing because of its bactericidal
effect. An applied low strength electric field enhanced the
killing action against Pseudomonas aeruginosa (47). There
is more evidence of antimicrobial effects of a small
applied electric field (48,49).
Antibacterial activity was also enhanced by H2O2 production at the anodal side in the presence of a low amperage (10–100 µA) direct electric current (DC). Bacteria
killed were Staphylococcus epidermis and Staphylococcus
aureus (48,49).
Further evidence of wound healing using electrical
stimulation is the orientation of newly synthesized
collagen (50). This process will take place even in the
absence of neural influences (50).
Bone-fracture healing
Worldwide more than a quarter of a million patients with
non-union fractures have benefited from the noninvasive effects of electric treatment (13).
Although the mechanisms, by which this therapeutic effect on bone-fracture healing is manifested, have
not yet been fully elucidated, many studies on the
effects of an electric field on basic bone cell processes
are increasing our understanding of the healing effects.
The inflow of Ca2+ into cells after exposure to a small
electric field activates many processes specifically
involved in the healing process of bone cells specifically (see Part 1).
Evidence of specific effects which may help to clarify
the bone-fracture healing process is the calcium-related
production and release of growth factors in bone cells;
including, PGE2, IGF-II TGFβ-1, discussed previously
(4,17,21,27). Another important paper on bone fracture
healing described that osteochondral repair was stimulated in a fresh fracture healing experiment (51).
Enhanced blood flow was also seen in this experiment
(51).
Pain alleviation
Pain has been treated successfully with applied electric
fields for many years. However, the cellular mechanisms
responsible for the decrease in pain perception remain, in
part, unresolved. Enhanced release of dynorphins and
enkephalins (especially increases of β-endorphins) in
experimental animals and in humans, exposed to low
(2 Hz) and moderate (100 Hz) frequencies has been implicated in raising of the pain threshold (1). It was shown by
Ulett et al. (1998) that electrical stimulation alone was as
effective in pain relief as electroacupuncture. Although
the role of substance P in the alleviation of pain after
electric treatment remains unclear, recent research indicated that the internalization of substance P receptors
may also contribute to the hyperalgesia experienced after
electric treatment (52).
Odendaal and Joubert showed that patients with
chronic back ache, due to osteoporosis, were successfully
treated with electric therapy (53). The effects of low
frequency electric stimulation on pain and mobility in
osteoarthritis patients were also studied (54). In this
study, patients responded positively to the treatment. DH
Van Papendorp et al. (2000) (55) showed a fourfold
increase in β-endorphin levels in patients with chronic
pain compared to healthy volunteers after electric
therapy.
Anti-inflammatory effects
Electrical therapy is used across the world for the relief of
pain and inflammation. Although widely used, the physiological action mechanism explaining the analgesic
effects is not perfectly clear. The mechanism of mid-range
frequency (100 Hz) treatment is usually explained by the
gate control theory of pain, while low frequency
(4 Hz) treatment is usually explained as due to the release
of endorphins. Recently Sluka et al. (1999)(1), showed
that the mid-range frequency (100 Hz) and low frequency
(4 Hz) application produced the analgesic effects through
different opioid receptors in arthritic rats. Both types of
electric treatment were 100% effective.
Enhanced local circulation
Apart from the possible contributing effects of electrical
therapy on blood flow specifically in wound healing, the
effect on local circulation in general has also been reported.
Again enhanced NO production was implicated (42,56).
Scott and McCormack (1999) (57) also showed that
electrical stimulated vasodilation in guinea-pig pulmonary arteries was mediated by NO. Enhanced peripheral micro-circulation reported by many (42,56–58) after
electrical stimulation may also contribute to improvement in inflammatory conditions in the treated area.
From the short discussion above it is clear that an applied
small electric field reduces pain and inflammation.
Electric therapy may also reduce local swelling because
of enhanced local circulation. All these factors may contribute to promote pain relief and enhance joint mobility.
Electric stimulation reduces pain in arthritic patients
In a multicenter, double-blind, randomized, placebocontrolled study, it was found that pulsed electrical stimulation was an effective treatment of osteoarthritis of the
knee. The device used was a portable, battery operated
device that delivers a mid-range frequency (100 Hz), low
amplitude, voltage sourced, monophasic, spiked signal to
the knee via skin electrodes (3).
A PHYSICAL MODEL FOR UNDERSTANDING THE
VARIETY OF HEALING EFFECTS ASCRIBED TO
THE APPLICATION OF AN EXTERNAL APPLIED
ELECTRIC FIELD
The most attractive proposal to explain the effects discussed in the prior parts of this paper is due to Tsong and
co-workers (5,31). This model suggests resonant coupling
between an oscillating electric field and changes in the
conformational state of membrane proteins involved in
signal transduction processes. In physical terms, each
type of membrane protein is an oscillating system that
may be driven by an applied electric field of the appropriate strength and frequency. A crucial element of this
model is the dramatic amplification of the applied electric
field in the cell membrane of an intact cell. This effect
allows the application of a benign electric field on the
macroscopic level, avoiding the dielectric breakdown of
H2O and chemical burning from taking place. Another
important aspect of this model is that a continuously
oscillating electric pulse is needed to effectively drive the
described signals to the cell. Furthermore, the complexity
of the chemical environment in the cell prescribes that
the most efficient driving frequency will show some variation along the dynamic changes occurring in the cellular
environment around the cell membrane.
Tsong (5) indicates experimentally how different transmembrane processes respond most effectively to oscillating electric fields of particular frequencies specific to
each particular cellular process.
Both a pulsed DC field and a sinusoidal AC field have
the required oscillatory character. However, an argument
may be made that the energy contained in a pulsed DC
field with short pulse width is more effectively concentrated than the energy distribution in an AC field. Direct
comparison of the two types of field is suggested to establish whether this is indeed the case.
In conclusion: the judicious application of the driven
oscillator model to the wealth of cellular transmembrane
effects discussed in this paper promises a rich harvest of
benefits to human health.
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