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J.A. Tuszynski, S. Portet, J.M. Dixon, C. Luxford and H.F. Cantiello: Ionic Wave Propagation Along Actin Filaments

J.A. Tuszynski, S. Portet, J.M. Dixon, C. Luxford and H.F. Cantiello: Ionic Wave Propagation Along Actin Filaments

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Ionic Wave Propagation along Actin Filaments
J. A. Tuszyn´ski,* S. Portet,* J. M. Dixon,* C. Luxford,* and H. F. Cantiello
y
*Department of Physics, University of Alberta, Edmonton, Alberta T6G 2J1, Canada; and
y
Massachusetts General Hospitaland Harvard Medical School, Charlestown, Massachusetts 02129 USA
ABSTRACT We investigate the conditions enabling actin filaments to act as electrical transmission lines for ion flows alongtheir lengths. We propose a model in which each actin monomer is an electric element with a capacitive, inductive, and resistiveproperty due to the molecular structure of the actin filament and viscosity of the solution. Based on Kirchhoff’s laws taken in thecontinuum limit, a nonlinear partial differential equation is derived for the propagation of ionic waves. We solve this equation intwo different regimes. In the first, the maximum propagation velocity wave is found in terms of Jacobi elliptic functions. In thegeneral case, we analyze the equation in terms of Fisher-Kolmogoroff modes with both localized and extended wavecharacteristics. We propose a new signaling mechanism in the cell, especially in neurons.
INTRODUCTION
The cytoskeleton is a major component of all living cells. It is made up of three different types of filamental structures,including actin-based microfilaments (MFs), intermediatefilaments (e.g., neurofilaments, keratin), and tubulin-basedmicrotubules (MTs). All of them are organized into net-works, which are interconnected through numerous partic-ular proteins, and which have specific roles to play in thefunctioning of the cell. The cytoskeletal networks are mainlyinvolved in the organization of different directed movementsin cell migration, cell division, or in the internal transport of materials. Polymerization of MFs is responsible for cellmigration and for the remodeling of the leading edge of cells.MTs attach to the chromosomes and mediate cell division.Molecular motors are protein complexes that are associatedwith the cytoskeleton and drive organelles along MTs andMFs in a ‘‘vectorial’’ transport.Actin is the most abundant protein in the cytoplasm of mammalian cells, accounting for 10–20% of the totalcytoplasmic protein content. Actin exists either as a globular monomer (Fig. 1), i.e., as the so-called G-actin, or asa filament, i.e., an MF: the globular monomers polymerizeinto polar two-stranded helical polymers, MFs, also calledF-actin. Under physiological conditions, actin filaments areone-dimensional polymers that behave as highly chargedpolyelectrolytes (Cantiello et al., 1991; Kobayasi, 1964;Kobayasi et al., 1964). The linear charge density of F-actin isestimated theoretically to be 4
3
10
3
e
 / 
m
m in vacuum, andalthough lower than that of DNA at physiological pH, it maysupport ionic condensation in buffer solutions as originallypredicted by Manning’s condensation theory (Manning,1978). This has recently been confirmed experimentally bylight scattering (Tang and Janmey, 1996) although other experimental work arrives at linear charge densities that are much higher (Cantiello et al., 1991) of order 1.65
3
10
5
e/
m
m. The latter value of charge density is consistent withother experiments and is associated with a highly uncom-pensated charge density of actin in solution. These experi-ments include the coexistence of different electric (Kobayasi,1964; Kobayasi et al., 1964) and magnetic (Torbet andDickens, 1984) dipole moments in F-actin, the anomalousDonnan potential, nonlinear electro-osmotic behavior of actin filaments in solution (Cantiello et al., 1991), and theability of F-actin to support ionic condensation-based waves(Lin and Cantiello, 1993).Many years ago, Manning (1978) postulated an elegant theory, which stated that polyelectrolytes may havecondensed ions in their surroundings. According to Mann-ing’s hypothesis, counterions ‘‘condense’’ along the stretchof polymer, if a sufficiently high linear charge density ispresent on the polymer’s surface. Thus, a linear polymer maybe surrounded by counterions from the saline solution suchthat counterions are more closely surrounding the polymer’ssurface, and co-ions of the salt solution are repelled such that a depletion area is also created. Some important details of theion distribution in polyelectrolytes regarding Manning’scondensation theory can be found in Le Bret and Zimm(1984). The sum of surface charges and associated counter-ions drops to values given by a formula that depends on thevalence of the counterions and the Bjerrum length. Thisparameter, in turn, is a phenomenological property of theion’s ability to compensate for the surface charges, depend-ing on the solvent and temperature of the solution. Bjerrumdeveloped a modification of the Debye-Hu¨ckel theory in1926 for ion-pair formation provided that the ions are small,they are of high valence, and the dielectric constant of thesolvent is small (see MacInnes, 1961, for a comprehensiveexplanation of derivations of relevant equations). TheBjerrum length is the distance at which the Coulomb energyof the screened charges equals
B
, the thermal energy,creating an equilibrium under which the charges would not preferentially move from that equilibrium. See Eq. 1 below.
Submitted July 16, 2003, and accepted for publication November 14, 2003.
Address reprint requests to J. A. Tuszyn´ski, E-mail: jtus@phys.ualberta.ca.J. M. Dixon’s permanent address is Dept. of Physics, University of Warwick, Coventry CV4 7AL, UK.
Ó
2004 by the Biophysical Society0006-3495/04/04/1890/14 $2.00
1890 Biophysical Journal Volume 86 April 2004 18901903
 
The cylindrical volume of depleted ions outside the cloudofionssurroundingthepolymer servesasanelectricalshield.Thus, the ‘‘cable-like’’ behavior of such a structure issupported by the polymer itself and the ‘‘adsorbed’’ counter-ions, which for all practical purposes are ‘‘bound’’ to thepolymer. The strength of this interaction is such that evenunder infinite dilution conditions (i.e., ionic strength
*
0), thecounterionsarestillattractedtothepolymeranddonotdiffuseout from the polymer’s vicinity. Although this theory wasoriginally postulated for such polyelectrolytes as DNA, thesame applies to highly charged one-dimensional polymers.Available atomic models of actin are largely derived fromthe crystal structure of the monomer and primary sequencing(Holmes et al., 1990; Kabsch et al., 1990) and not fromactin’s behavior in solution. Thus there is the possibility of other explanations to reconcile the discrepancy betweentheoretical and experimentally determined charge densitiesof actin. This could include highly nonlinear interactionsbetween the hydrated molecule and its surrounding counter-ions, which are not taken into account in the atomic modelsabove and which may play an important role in theelectrodynamic properties of proteins in solution (Rullmanand van Duijnem, 1990). It is to be expected, for example,that, because of the helical nature of the F-actin (Holmeset al., 1990), the distribution of counterions will benonuniform along the polymer’s length. As a consequence,spatially dependent electric fields could be present andarranged in peaks and troughs as originally postulated byOosawa (1971). This might imply large changes in thedensity of small ions around the polymer with a largedielectric discontinuity in the ionic distribution (Kabschet al., 1990; Anderson and Record, 1990).The double helical structure of the filament providesregions of uneven charge distribution such that pockets of higherandlowerchargedensitymaybeexpected.Thechargedistributioncanbeenvisionedasastringofcolabottlesinsideanelastic tube.Asthebottlesarepushedintothecylinder,theouter shape of the wider parts of each bottle may provide theshortest distance to the cylinder’s wall, and thus the thinnest charge density. The thinner sections of each bottle provide‘‘deeper’pockets where more ions can be trapped. Thedistance between ion clusters in the pockets, which in realityare immersed in water with very specific properties noshared by the bulk solution, will make ions move up anddowntheslopesofthesurfaceofthebottle.Thisunevenionicdistribution along a short stretch of the polymer (likely theaverage pitch 35–40 nm) may be considered a linear unit of the circuit to be modeled. This ionic distribution makes twoessential contributions to the nonlinear electrical componentsof the model. First, the nonlinear capacitor, which isassociated with the spatial difference in charges betweenthe ions located in the outer and inner regions of the polymer.Second, any charge movement tending to dissipate this localgradient (reversibly) generates a secondary electromotiveforce due to the charge movement, namely a local current.This is the main contribution to the inductance of the singlestretch of polymer.F-actin, being a highly charged polyelectrolyte, containsa fraction of its surrounding counterions in the form of a condensed cloud about its surface. Such a cloud may behighly insensitive to large changes in the ionic strength of thesurrounding saline solution (Oosawa, 1970; Manning, 1969;Zimm, 1986).The Bjerrum length,
l
B
, describes the distance beyondwhich thermal fluctuations are stronger than the electrostaticattractions or repulsions between charges in solution whosedielectric constant is
e
. It is defined by
e
2
4
ee
0
 l
B
¼
B
(1)for a given temperature
in Kelvin. Here
e
is the electroniccharge,
e
0
the permittivity of the vacuum, and
B
isBoltzmann’s constant. For a temperature of 293 K, it isreadily found tha
l
B
¼
7.13
3
10
ÿ
10
m. Counterioncondensation occurs when the mean distance betweencharges,
b
, is such that 
l
B
 / 
b
¼
S
[
1. Each actin monomer carries an excess of 14 negative charges in vacuum, andaccounting for events such as protonation of histidines, andassuming there to be 3 histidines per actin monomer, thereexist 11 fundamental charges per actin subunit (Tang andJanmey, 1996). Assuming an average of 370 monomers per 
m
m, we find that there is
;
4
e
 /nm in agreement with anearlier statement. Thus we expect a linear charge spacing of 
b
¼
2.5
3
10
ÿ
10
m, so
S
¼
2.85. As the effective charge,
q
eff 
,or renormalized rod charge is the bare value divided by
S
, wefind
q
eff 
¼
3.93
e
 /monomer.Assuming for simplicity a linear charge distribution about the actin filament, the linear charge density,
, is much
FIGURE 1 Ribbon diagram of an actin monomer (Kabsch et al., 1990)(Protein Data Bank identification: 1ATN). Figure produced with RasMol.
Ionic Wave Propagation along Actin 1891Biophysical Journal 86(4) 1890–1903
 
greater than 1/ 
z
, where
z
is the valence of the counterions insolution. The parameter,
, is given by
¼
e
2
4
e
0
e
B
Tb
;
(2)where
e
is the electronic charge,
e
the dielectric constant of water, and
b
the average axial spacing of charges onthe polyelectrolyte (Zimm, 1986). The parameter,
, wascalculated to be 110 for actin filaments (with
z
¼
1 for H
1
andK
1
ions) and so
)
1
=
z
(Lin and Cantiello, 1993). Thus
;
99% of the counterion population is predominantlyconstrained within a radius of 8 nm (Pollard and Cooper,1986) round the polymer’s radial axis (Zimm, 1986).Significant ionic movements within this ‘‘tightly bound’ionic cloud are therefore allowed along the length of the actin(Fig. 2), provided that it is shielded from the bulk solution(Oosawa, 1970; Parodi et al., 1985).The electro-conductive medium is a condensed cloud of ions surrounding the polymer. To be electrically insulatedfrom the bulk of the solution (although not mandatory), thereshould be some sort of shielding from the bulk solution,which acts as a common ground to the ‘‘transmission line’’.The presence of one or more layers of waters of hydrationaround the protein filament may provide additional screen-ing. In earlier publications (Hameroff et al., 2002; Haganet al., 2002), some of the present authors have suggested that such a condensation/ionic cloud/plasma phase aroundmicrotubules may help shield not only signaling buquantum states from external decoherence. In this connec-tion, the transfer of information by quantum coherence-based phenomena requires that the system be isolated fromthe environment such that the ‘‘energy’’ does not dissipate.This would imply that efficient transfer of energy from‘energized groupsthat can only be in resonatingfrequencies when they are close to each other (Davydov,1982; Fro¨hlich, 1975, 1984). In the context of microtubular ‘‘kink’’ soliton behavior, the calcium ions adsorbed to oneregion of each tubulin monomer may form a functionaldipole, which is shifted in space by energizing the monomer by GTP binding (Sataric et al., 1993). The dipolar momentsof each heterodimer (
a
-,
b
-tubulins) would be switched inthe microtubule, such that a change in structural localstability is transferred spatially along the microtubular structure. This is the basis of the proposed informationtransfer mechanism, which although highly probable, isdifferent from the ionic waves supported by actin filaments.It is important to note, however, that ionic waves might alsobe supported by microtubules, a phenomenon that will re-quire experimental proof. Furthermore, quantum modelssupported by microtubular structures might also exist that imply a particular state of water in the microtubular structurethat indeed has properties largely different from those ex-pected by free solution (see Mavromatos, 1999).Bearing in mind the sheath of counterions around the ac-tin filament, we see that effectively actin polymers may act as biological ‘‘electrical wires’’, which can be modeled asnonlinear inhomogeneous transmission lines that are ableto propagate nonlinear dispersive solitary waves (Kolosicket al., 1974; Ostrovskii, 1977) in the form of solitons(Lonngren, 1978; Noguchi, 1974). It has been proposed that such solitons, localized traveling waves, exist in manybiological systems and, in fact, have earlier been postulatedin linear biopolymers such as MTs (Sataric et al., 1993) andDNA (Baverstock and Cundall, 1988). Interestingly, bothsolitary waves (Lin and Cantiello, 1993) and liquid crystalformation (Coppin and Leavis, 1992; Furukawa et al., 1993)have been observed in actin filaments possibly providinga potentially fruitful environment for innovative biotechno-logical applications.In this article we develop a model based on thetransmission line analogy with inductive, resistive, andcapacitive components. The physical significance of each of the components, for each section of the electrical network,will be described below. This way we will investigate thenature of nonlinear ionic waves propagating along an actinfilament in solutions containing counterions as would befound under realistic physiological conditions.
FIGURE 2 Nonlinear dispersivesolitary wavestravelingalong an actin filament.
1892 Tuszyn´ski et al.Biophysical Journal 86(4) 1890–1903

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