AM. ZOOLOGIST, 2:5-25 (1962).
COMPARATIVE PHYSIOLOGY OF CONDUCTION IN
NERVE AND MUSCLE
C. HOVI.K
Department of Zoology, University of (llasgow
INTRODUCTION
It sometimes helps us to understand a
natural mechanism more deeply if we consider its function teleologically and I hope
you will permit an introductory recourse to
this approach. A nerve fiber must be able
to transmit a message, or as we now say, a
quantity of information, in the form of a
code, over distances varying from less than
a millimeter (in the case of a small insect)
up to several meters (in the case of a large
whale). This has to be achieved with minimal loss of accuracy. To do this the nerve
cell uses its capacity for producing propagated electrical potential changes. Speed as
well as accuracy is desirable; faster conduction permits the evolutionary development
of larger, more complex and efficient organisms.
In principle, a system using signals individually graded in regard to both magnitude and time-course (like the message in a
telephone cable) would transmit information most economically and swiftly. But
this demands a capacity for accurate reproduction at all points along the length of the
nerve. Even a highly stable, well-insulated
telephone cable is unable to do this, and a
long one requires "booster" stages at intervals. Biological systems are notoriously full
of randomly-fluctuating or "noisy" elements
and so can be expected to have difficulty in
maintaining the degree of accuracy desired.
They are very badly insulated and need
continuous "boosting" along their length.
It is not surprising, then, that nerve fibers
have adopted—uniformly as far as we know
at the present time—a system of coded signalling in which the transmitted unit is a
simple, all-or-nothing pulse and so indicates
merely "on" or "off," as do the functional
units of a digital computer. There is no
message in the pulse itself except this indication; the primary coding of the message
Author's present address: Dept. of Biology, University of Oregon, Eugene, Oregon.
(5)
in the nerve is contained in the duration of
the intervals between successive pulses. It
cannot be emphasized too strongly that this
method is unlike that used by computers,
for unlike computers, the nervous system
must in effect utilize an accurate clock with
which to compare the arrival of these signals, in order to interpret their message.
The amount of information which can be
transmitted in unit time by a pulse-time
system is increased if the signal itself is very
brief, and hence the nerve impulse must be
of short duration.
Muscles receive instructions from their
motor nerves in the form of these all-ornothing impulses, coded so as to be translated by the muscle into controlled contraction. It is at this point that we see how a
coded message is interpreted and translated
into functional terms, in this case the development of force and movement by the
muscle. If the signals were handed on to
the contractile machinery unaltered, all-ornothing excitations of the contractile
mechanism would result. In order to grade
tension development the muscle would then
have to adopt one of two possible alternatives. The simplest is to break down the
contractile mechanism into small steps, each
actuated by an all-or-nothing signal. The
alternative is to break down the muscle into
separately-innervated sub-units, each of
which can be included or withdrawn independently from participation in contraction. Each method has certain disadvantages. The former must cause a reduction
in the maximum speed of response by the
muscle to nervous command, owing to the
time required for summation of the small
steps, though it might well be adequate for
some situations. The latter is quite sound
in principle but it is intrinsically unsuitable for small muscles composed of few
fibers since the number of sub-units into
which a small muscle can be divided is
small. Nevertheless, it has been utilized by
G. HOYIE
many muscles, especially in vertebrates.
A quite different type of control is possible in principle, and that is to have a dual
or multiple mechanism for each muscle
liber. One channel may then be used for
exciting very large contractile responses, another for giving graded responses. It should
be possible to do this with a common contractile mechanism, if this in turn can be
activated in a graded fashion; but it would
certainly require dual or multiple innervation of each muscle fiber, with corresponding dual or multiple transmission mechanisms. Then one nerve could be used when
the fastest response is called for and another for slower responses requiring careful
gradation. In spite of the complication in
innervation and mechanism, this method is
widespread throughout the animal kingdom; phylogenetically it may well be the
oldest. It is the one almost exclusively utilized in arthropods, for it permits excellent
control with only two nerve fibers per
muscle and arthropods, especially small
ones, have very few nerve fibers to utilize.
Employment of graded responses does, however, lead to the difficulty of initiating and
propagating a variable-sized signal in the
muscle fiber membrane. This has been partly overcome by carrying the coded nerve
message to all parts of the muscle fiber via
nerve branches. Each nerve-ending liberates an approximately similar quantity of
transmitter-substance, which is adequate
only for the production of a small, local
electrical change (post-synaptic potential).
Post-synaptic potentials (p.s.ps.) are graded
in height, depending on the quantity of
transmitter released. The muscle membrane
in the multiply-innervated type of system
must then be without the capacity for responding to the graded post-synaptic potentials with all-or-nothing signals. It may lose
its electrical excitability completely, as has
the slow skeletal muscle of the frog. Or it
may reduce its responsiveness from all-ornothing to a graded nature, so that the electrical response of the muscle fiber membrane is a function of the size of the postsynaptic potential. In that way a varied
range of information is transmitted by single signals, the graded p.s.ps. Integration,
or initial translation of the signal messages,
is then achieved at the synapse. The height
of a post-synaptic potential depends on the
interval between it and the immediatelypreceding signal, and on other aspects of recent history of the junction. Like all transmissive stages utilized by the nervous system p.s.ps. are intimately linked with the
time-clock.
There are two other places in the nei-vous
system where graded, rather than all-ornothing, responsiveness is desirable in principle and in fact found. Firstly, in sensory
nerve terminals, many fine branches may
converge on a single axon, so that if each
gave discrete all-or-nothing signals a chaos
of impulses would pass into the main trunk.
An initial section of the main trunk acts as
an integrating region and impulses originate there, but the signals arising in the
branches are graded. Secondly, in the dendritic branches of central nerve cells (and
in some cases the nerve cell bodies) which
receive multiple synaptic contacts, possibly
from many cells, a similar argument applies.
The post-synaptic potentials are graded responses and impulses originate in the axon
hillock region. The dendrites are probably
not electrically excitable.
Since the cells of the nervous system are
discrete units it is necessary for them to be
able to transmit excitatory events among
themselves, and also to the muscle cells. To
this end special forms of contact (synapses)
occur between them. The transmissive process at these points is usually chemical in nature. In one instance very close physical
contact between adjacent nerve cells permits electrical transmission (Furshpan and
Potter, ^59) but this is probably very rare.
The giant axons of earthworms, unlike
those of the squid, are formed by the fusion
of segmentally-produced units in which the
points of contact remain partitioned. At
these points of contact the transmission is
also electrical in nature (Kao and Grundfest, 1957).
We may now summarize the major requirements of excitable membranes of different nerve and muscle cells, or different
parts of these cells as follows:
1. Axons of nerve cells must produce rap-
CONDUCTION IN NERVE AND MUSCLE
idly-propagating, brief, all-or-nothing electrical signals.
2. Muscle cells may be required to produce signals comparable to nerve impulses,
or they may be required to give only graded
electrical signals in response to electrical
stimulation, or they may be electrically unresponsive to electrical stimulation.
3. Regions of nerve or muscle cells underlying special points of contact (synapses)
from nerve cell branches must be capable
of responding by giving electrical changes
to chemical substances released by the terminals.
In summary, four different capabilities
are called for: all-or-nothing pulsatile responsiveness, graded electrical responsiveness, electrical unresponsiveness, and responsiveness (by electrical change) to chemical stimuli.
THE NATURE OF ELECTRICAL ACTIVITY
IN NERVE AND MUSCLE CELLS
Our problem is to discover how excitable
cells can provide for each of these different
functions. We may assume that they probably have achieved this result by a process
of evolution starting from a common ancestral cellular mechanism. A general theory
of impulse activity in nerve and muscle was
first produced in 1902 by Bernstein. By that
time the all-or-nothing, brief nature of the
nerve impulse had been established and it
was thought that a similar impulse was utilized in muscles. According to Bernstein,
the impulse is due to a brief, temporary obliteration of a resting membrane potential.
The latter is produced across a (at that
time hypothetical) semi-permeable plasma
membrane, a layer of differentiated cytoplasm about 100 A thick forming the functional skin of the nerve fiber or muscle cell
and containing within it the fluid and structural components of the cell. The resting
voltage could be measured, albeit reduced
in magnitude by short-circuiting, between
an electrode placed on the outside of a
nerve or muscle and a second one placed in
a freshly-made cut, which permitted fairly
good electrical contact with the inside of
the cells. This potential difference approximated 1/10 volt in the best measurements
(Tschachotin, 1907). It was reduced progressively by gradually raising the external
potassium ion concentration of the bathing
fluid.
Bernstein made this observation the basis
of his hypothesis. The interior of both
nerve and muscle cells contains a high concentration of potassium ions; the fluid surrounding the cells in the body does not, for
sodium is the major cation. Potassium ions
must, therefore, be accumulated by the cells
and sodium excluded from them. Chloride
ions form the major anion in the body fluids but are virtually absent from the inside
of the nerve or muscle cell. Hence, Bernstein proposed that the membrane is not
permeable to sodium or chloride but markedly so to potassium ions. The major internal constituents of the cells must be protein, which at the pH of the cells is in anionic form. These large anions are unable
to diffuse out across the cell membrane and
so a dynamic equilibrium is established; potassium ions enter the cells to neutralize the
negative charges on the immobile internal
anions, but tend to move outwards down
the concentration gradient. The tendency
to move outwards is just balanced by a
small net negative charge on the interior.
At equilibrium, which will quickly be
established if the ionic permeabilities are
not too low, the potential difference will approach the theoretical potential for a potassium concentration cell (potassium equilibrium potential). The first theoretical
treatment of this kind of system had been
due to Donnan, and the state was named
after him a Donnan equilibrium. The value
of the potential difference was determined
theoretically by Nernst (1911)
as:
Em = RT/F logft [Ki]/[Ko]
(Nernst equation)
R = gas constant
T = absolute temperature
F = Faraday's constant
[Ki] = potassium activity inside cell
(approximately = concentration)
[Ko] = potassium activity outside cell.
Following excitation, according to the
Bernstein hypothesis, the membrane struc-
G. HOYLE
ture would be temporarily altered, affecting
the general permeability to all ions. Sodium
and chloride would be permitted to enter
and potassium would leave. The resting potential would fall towards zero, the whole
membrane behaving like an injured one.
The time-course of this change must be extremely rapid, occupying barely one millisecond. But even more remarkably, recovery occurs in an only slightly longer period.
This was supposed to be simply due to an
immediate return of the original properties
of the membrane.
As an explanation of resting and conducted activity in nerve and muscle this hypothesis lasted unchanged for almost four
decades. The possibility of chemical activation at synapses did not become fully established until about the end of this era. Most
of the later experiments designed to test the
hypothesis confirmed its probable validity,
although alternative theories were proposed. One alternative theory was that the
resting potential was directly associated
with metabolic activity, perhaps in the
form of a redox potential. Since the possible nature of this activity was not specified
in detail, the theory has not offered any serious challenge to the ionic model. The action potential has often been regarded as
having a pharmacological basis in terms of
a highly active organic substance (commonly regarded as acetylcholine) moving inwards across the membrane (Nachmansohn, 1959). There might well be some such
release and movement in connection with
the structural changes, but these would not
invalidate the general hypothesis, because
the ionic gradients and currents of action
due to the concentration-cell effects of unequally-distributed mineral-ions would still
play the fundamental role in conduction.
The Bernstein hypothesis underwent a
setback when it was found that the resting
membrane is in fact permeable to sodium
ions (Fenn, 1940), but this difficulty was
soon countered by endowing the membrane
with a "sodium pump" capable of ejecting
intruding Na+ ions as fast as they enter
(Dean, 1941). A much more serious blow
was delivered when the first directly-recorded membrane potentials were meas-
ured. These were obtained following the
introduction of the squid giant axon by
Young, (1938) which permitted measuring
the membrane potential of a single nerve
fiber with the aid of an electrode directly
inserted inside it. Cole and Curtis (1939)
used this method to show that there is in
fact a marked fall in membrane resistance
during the action potential, as predicted by
the Bernstein theory. But these, and other
investigators (Hodgkin and Huxley, 1939)
were in for a big surprise when they looked
at the action potential, for it turned out
that this did not simply fall to zero, as proposed by the theory, but actually reversed
in sign by an appreciable amount. It is not
possible to detect a reversal of membrane
potential using external electrodes only.
The second world war interrupted further research on the nerve impulse for a
few years, but soon after a penetrating attack was initiated by the British group.
Starting with the Bernstein hypothesis as
their basis, they considered the possibility
that by including the sodium ion in the formation of the action potential it might be
possible to explain the observed course of
events. As early as 1902, in the same volume
of Pfliigers Archiv as that in which the
Bernstein hypothesis was stated, Overton
had proposed that sodium must be involved
in the action potential and might be exchanged for potassium. Since the simpler
Bernstein theory seemed perfectly adequate
the Overton proposals were neglected. If
the membrane were suddenly made permeable to sodium ions selectively, argued
Hodgkin (1949), the inequality of distribution of these ions across the membrane
would certainly ensure a fall in resting potential. Furthermore, the equilibrium potential for sodium ions is of opposite electrical sign to potassium. This meant that
if the sodium ion permeability change were
sufficiently drastic, so that relative to the
other ions it made a very large contribution
to the potential, there could be a reversal
of membrane potential. The voltage on the
membrane would swing from a value close
to the equilibrium potential for potassium
to that of the equilibrium potential for sodium (Fig. 1). Visualizing the possibility
CONDUCTION IN NERVE AND MUSCLE
RESTING MEMBRANE
ACTIVE MEMBRANE
V
Drastic rise in
Na conductance
FIG. 1. The "ion-batteries" underlying electrical activity. At rest the potassium battery (En) dominates
the membrane potential (Em) owing to a relatively
high potassium conductance (gk). Following excitation the sodium conductance (gN«) undergoes a
drastic rise and so the sodium battery (ENn) comes
instead to determine the membrane potential. An
increase in chloride conductance (gcl) would act in
the opposite direction to sodium.
of a specific chemical transporting or carrier mechanism, the phenomenon of sodium permeability increase was termed sodiwn activation, the carrier mechanism in
effect being activated.
The principal consequence of this hypothesis is that the magnitude of the action
potential and, in particular, that of the
overshoot, should depend on the external
concentration of sodium ions. Hodgkin and
Katz (1949) showed that this is true for
squid giant axon and soon after it was demonstrated for frog sartorius muscle (Nastuk
and Hodgkin, 1950). Since then it has been
demonstrated to apply to mammalian and
a number of other nerves and muscles
(Shanes, 1958a,b—review). The fall in magnitude of the action potential occurs in accordance with the equation:
V = 58 log "Na-substitute'yNao
where "Na-substitute" is the concentration
of an "inert" ion substituted for sodium.
The rate of rise of the action potential
should, and does, also fall as the external
sodium concentration is increased.
The new explanation of the recovery
phase of the action potential also differs
from the original Bernstein one, which postulated a simple return to status quo in regard to the general ionic permeability of
the membrane. The new hypothesis proposed a specific increase in permeability to
potassium ions, occurring soon after the sodium permeability increase, but with a delayed rise. This may be called potassium
activation. By itself potassium activation
would not cause a return to the resting potential if the sodium conductance remained
high, so a further effect was proposed, to
ensure a cutting off of the inward current
due to sodium ions. This was termed sodium inactivation, and visualized as a sudden stoppage of the inward sodium ion
transport mechanism. As the membrane becomes charged again during the period in
which K+ flows outwards, the potassium
conductance may be expected to fall automatically, so it is not necessary to postulate
specific inactivation in addition, although
this might occur.
On this new hypothesis the time-course
of the action potential is determined by the
G. HOYLE
10
calculated
action potent ial
which alter the ionic permeabilities and so
also the effective membrane resistance. The
machine produces an oscillographically-displayed current which exactly matches that
flowing across the membrane and so parallels the permeability changes (Hodgkin and
Huxley, ]952a,b)
By measuring the current changes with
time, first in the presence of a normal concentration of external Na and second in its
absence, and subtracting the second values
FIG. 2. Ionic changes underlying the action potential of the squid giant axon. The actual conduct- from the first, the time-course of the sodium
ance changes to the sodium and potassium ions as current can be determined. This current
determined by the "voltage clamp" method are starts immediately the voltage across the
given by solid lines. The calculated action poten- membrane is displaced in the depolarizing
tial based on these conductance changes is given by direction and rises rapidly to a peak in 0.5
the broken line. The action potential starts in advance of the local conductance changes owing to msec, returning to zero inside four msec
the electiotonic spread of current in advance of the (Fig. 2). The current is in the inward (depermeability changes. (From Hodgkin and Huxley, polarizing) direction and thereby assists the
1952&, J. Physiol.)
applied voltage. In the absence of sodium
the current is entirely in the outward direcsum of the sodium-ion and potassium-ion tion and is considered to be carried very
conductance changes, along the lines illus- largely by potassium ions. In the squid
trated in Fig. 2. The great advantage of this giant axon it starts to rise as soon as the
hypothesis was that it was possible to sub- voltage is lowered, but at a much slower
ject it to experimental tests, especially on rate than that for sodium, and it takes
the squid giant axon. There should be a many milliseconds to reach completion. By
net gain of sodium ions about equalled by taking the measured values for Na conducta net loss of potassium ions during the pas- ance changes and combining them with the
sage of a nerve impulse. By using Na24 and K conductance changes a theoretical action
K4- as tracers Keynes (1951) was able to potential can be constructed. This has a
show that a squid giant axon takes up about time-course which is in good agreement
3.7 p. /A mol Na ions per sq. cm. of mem- with the actual action potential.
In some recent experiments it has been
brane per impulse, while it loses 4.3 /j. ^
mol K ions per sq. cm. so that the gain in found possible to verify the ionic hypothesodium is balanced by the loss in potassium sis for the squid giant axon in a satisfying
way. On this hypothesis, solely the surface
as predicted.
The actual sodium- and potassium-ion membrane is concerned with conducted acconductance changes were measured by an tivity and the core is important only as the
ingenious device called the 'voltage clamp.' storehouse for potassium ions. If the axoIn this technique two electrodes are in- plasm can be squeezed out without doing
serted down the center of the axon and a irrecoverable damage to the surface mempre-determined voltage is applied suddenly brane it should be possible to replace it
across it by passing current through one of with a simple potassium salt solution of apthem from an amplifying device regulated propriate concentration and obtain normal
by feed-back from the actual membrane resting and action potentials. This has now
voltage, which is recorded from the other. been achieved (Baker, Hodgkin, and Shaw,
The electronic device measures the inten- 1961) using potassium sulphate or potassity and time-course of the current which sium isethionate under 2-3 cm hydrostatic
the machine has to provide in order to pressure, in the cannulated giant axon of
maintain constant voltage in the face of Loligo forbesi. The resting potential is prochanges taking place in the membrane portional to the logarithm of the inter-
11
CONDUCTION IN NERVE AND MUSCLE
nal potassium (sulphate)-ion concentration
when the external potassium concentration
is kept constant, as required by the theory
(Fig. 3). When sodium ions were used to
replace part of the internal potassium, the
resulting action potential was also reduced
in height as predicted.
Conducted action pote7itials in insect
nerves. The explanation of the nerve action potential outlined above seemed to be
D
-60
-C
—=2
-o
•
-50
tiali
£ -40
[K]0 = 10mM
^>
g -30 -
1
/
•3 -20
.2
« -10
0
+ 10
—i
A1
i
i
i
1
600
i
500
100
200
300
400
Internal potassium concentration (mAf)
mV.
+ 50
0
FIG. 3. Experiments on squid giant axons from
which all the axoplasm has been extruded, and refilled with artificial salines. Upper: effect of internal potassium concentration on resting potential of
axon bathed in sea water. Lower, left: upper, action
potential (internal electrode) with isotonic potas-
1
2
3
4
5
msec.
6
7
8
sium sulphate as internal medium; lower, normal
axon. Lower, right: effect of replacing some of internal potassium by sodium ions. A—normal, B—
25% replaced, C—50% replaced. (From Baker et
al., 1961, Nature.)
12
G. HOYI.K
Direction of impulse
Local current
after potential
Local current
FIG. 4. The propagating action potential. Left:
distribution of the wave of electrical disturbance
along the nerve fibre showing way in which electrotonic current flows from resting region into active
region and in so doing depolarizes in advance of the
main wave. Right: appearance of action potential
wave as recorded oscillographically with an internal electrode. Local current initiates spike when
threshold is exceeded.
capable of wide application, but not to phytophagous insects. In them the blood (hemolymph) sodium and potassium concentrations may be present in inverse ratio
compared to that in all other body fluids,
there being high potassium and a low sodium concentration (Bone, 1944). Nevertheless, the insect nerve action potential has
been found to be dependent on the presence of sodium, or a suitable sodium-substitute, and the recovery of normal membrane
potential can only occur in a low external
potassium concentration (Hoyle, 1953; Yamasaki and Narahashi, 1959a). Evidently a
normal ionic mechanism is utilized, but the
axons are surrounded by a sheath which
keeps out (or actively extrudes) potassium
ions while retaining sodium ions. (Hoyle,
1952; Twarog and Roeder, 1956)
spread of the potential evoked away from
the site, decreasing exponentially with distance. If the action potential mechanism is
blocked, for example by intense cold, this
purely electrical spread can be detected beyond the block (Hodgkin, 1937). It is this
action, spreading in advance of the wave of
permeability change, which acts as a stimulus to further depolarization and the initiation of progressive, propagated change (Fig.
4). The membrane in the wake of the advancing depolarization wave is still recovering its resting potential (and excitability) after the wave has passed too far away
to re-excite it. Otherwise the whole membrane would change permanently from the
polarized to the depolarized state. A long
nerve fiber can carry several impulses at the
same time, spaced 2-3 cm apart.
CABLE THEORY AND LOCAL-CIRCUIT ACTION
SALTATORY CONDUCTION IN MYELINATED
NERVE FIBERS
The general theory described above accounts for the changes which occur in active nerve fibers but it does not explain the
process of propagation. The theory for this
is that the membrane has certain passive
electrical properties which permit purely
electrical (electrotonic) conduction of an
applied potential change. The membrane
has the property of a condenser and electric
charge tends to spread along it evenly. But
it also has a finite transverse resistance so
the charge must leak away in time. Following activation at a given site, there is a
In myelinated nerve fibers of vertebrates
the electrical resistance of the myelin is so
high that local electrotonic spread of current across it cannot occur to the extent
necessary for initiation of further activity.
Nor is there sufficient space for these currents to pass underneath it. Instead, the current flows round the myelin and through
the nearest gap, i.e., the node of Ranvier.
The nodes are sufficiently close to each
other to ensure a reasonable safety-factor
for the depolarization produced, in exceed-
CONDUCTION IN NERVE AND MUSCLE
Membrane under
myelin remains
inactive
Outward current
depolarizes next
node of Ranvier
13
the same shape as that of the squid giant
axon. That of the frog sartorius muscle
fibers is similar in shape, but on a slightly
slower time scale. Differences of this order
of magnitude can be accounted for largely
on the basis of a longer electrical time constant (product of transverse resistance and
Current flows
capacitance) of the membrane, which will
Reverse ' potential
^ outside myelin
at active node
slow down the electrotonic rise and decay.
BIG. 5. Conduction in myelinated nerve fiber. Only
By contrast muscle fibers of hearts have
the membrane in nodal regions becomes active.
very
differently shaped action potentials
Current flows frorn the next nearest resting node
(Draper and Weidmann, 1951; Irisawa et
back over the outside of the myelin and returns in
the core of the fiber.
al.; 1961). The rising phase occurs similarly
and goes straight into an overshoot, but aling the threshold for firing the sodium-cur- though repolarization starts immediately
rent avalanche. The spread of simple elec- following the peak of the action potential
trotonic current is much more rapid than it soon slows down markedly, forming a
the propagation of action potentials in bare plateau which lasts for some 300-400 msec.
membrane, so faster overall conduction is The plateau has an important functional
achieved. The reversed membrane poten- significance. Once a nerve or muscle fiber
tial associated with full sodium activation of the ordinary kind has recovered its full
is developed only at the nodes; hence the resting potential following activity it is caaction potential as it were "jumps" from pable of being again excited so as to give
node to node, a process therefore referred another action potential. In muscle the recovery time is short compared with the duto as saltatory conduction.
The events occurring at the node itself ration of a twitch, and this permits the fuappear to be substantially the same as those sion of contractions leading to the very usefound in the squid giant axon. The rising ful tetanus. For a heart muscle to go into
phase of the action potential is certainly tetanus would, however, spell disaster for
due to sodium-ion entry. There is, how- most animals and a mechanism ensuring a
ever, some doubt as to whether the mem- period of inexcitability between contracbrane resting potential is a potassium con- tions sufficient to allow full relaxation, is
centration potential, and this has been cate- clearly desirable. This is" the purpose of the
gorically denied recently (Stampfli, 1959). plateau. How is it achieved?
Instead, it may be dominated by the chloIt can be shown experimentally that the
ride ion. This would not invalidate the duration of the plateau is greatly affected
general theory, on which the chloride ion by the external potassium-ion concentramay easily be expected to be able to replace tion (Weidmann, 1957). Also, the height
potassium as a source of resting voltage. In of the overshoot is reduced by lowering the
many muscle cells the chloride ion probab- external sodium-ion concentration (Weidly makes a major contribution (Hodgkin mann, 1957). Thus it is possible to explain
and Horowicz, 1959). Chloride-ion permea- the rising phase on the normal basis of a
bility increases are probably involved in specific increase in sodium conductance (socertain kinds of inhibitory activity and may dium activation) and the sharp peak as due
be associated with increases in membrane to sodium inactivation. Meanwhile the popotential. They can act in a similar man- tassium conductance is rising only very
ner to potassium as a restorer of resting po- slowly, but after about 300 msec starts to
tential.
rise rapidly, so bringing the plateau to an
end and depolarizing the fiber (Fig. 6).
OTHER KINDS OF CONDUCTED POTENTIALS,
This does not mean that a final solution of
HEART MUSCLE
the nature of the potential changes in heart
Not all propagated action potentials have muscle fibers has been reached, but merely
Direction
on of
impulse
14
G. HOYLE
O
100
20O
300
4.00ms
FIG. 6. Typical action potential from heart muscle
fiber and time-courses of hypothetical sodium and
potassium conductance changes which could underly it.
that changes in ionic permeability, if suitably timed, could explain them.
PACEMAKER ACTIVITY
Another feature of heart muscle cells is
their spontaneous "pacemaker" depolarization. Of course it is not difficult to simply
postulate a fluctuating conductance to one
of the ions. The equations derived by
Hodgkin and Huxley (19526) to describe
the action potential in terms of ionic conductance changes include a value m which
is a variable describing sodium activation.
Noble (1960) has shown that merely by inserting in these equations a different, appropriate value for m, the system is made
theoretically unstable during diastole. The
instability would be of the kind required
to lead to pacemaker activity.
GRADED RESPONSIVENESS AND DECREMENTAL
CONDUCTION
Electrical responses which are graded,
not all-or-nothing in magnitude, can be obtained from the normal nerve membrane
discussed previously, but only over a very
narrow range of depolarizations, just below
the threshold for the initiation of conducted spikes. They can readily be obtained
from fatigued, damaged, anoxic or lightly-
poisoned membranes. This section is, however, concerned with those membranes in
which gradedness is the normal situation,
for functional reasons. Subsynaptic membranes are always gradedly responsive to the
chemical substances which actuate them,
the magnitude of the response being a function of the concentration of the transmitter
agent liberated in their vicinity. It appears,
however, that they are not electrically excitable (Grundfest, 1957) and so they cannot conduct the resulting potential changes
except in so far as electrotonic spread occurs. The slow skeletal muscle fibers of the
frog are formed exclusively of this kind of
membrane (Burke and Ginsborg, 1956).
Functionally significant, gradedly-excitable electrogenic membrane occurs in nerve
in post-synaptic dendrites and possibly in
some pre-synaptic ones (Grundfest, 1960).
It also occurs in fine sensory nerve terminals (Grundfest, 1960). In all these cases
its function is to permit integration of incoming signals, in the former converting
coded information from digital-time to analogue-time form.
In muscle this kind of membrane is best
known from the arthropods, where it is
probably the only type present. It is, however, probably widespread throughout the
invertebrate phyla (Hoyle, 1957) and in
vertebrates it may occur in fish (Takeuchi,
1960), birds (Ginsborg, 1960) and in the
contractile portions of some intrafusal
muscle spindles in mammals (Boyd, 1958).
Membrane which is electrically excitable
but gives only graded, not all-or-nothing
responses is characterized by responsiveness
to depolarizing electrical stimuli over a
wide range of magnitudes, even exceeding
the resting potential. The responses may
go as far as the full overshoot position (sodium equilibrium potential), but at no
stage does the response become regenerative. Although the excitation initiates a
response in adjacent regions of the fiber the
latter is always smaller than the stimulus.
The process is illustrated in Fig. 7 and
should be compared with the all-or-nothing
situation. Such a response is conducted actively, but with a progressive decrement, so
that it rapidly decays to zero, as it propa-
CONDUCTION IN NERVE AND MUSCLE
Graded spike
responses
--n-rrm--Vt-
threshold
FIG. 7. Graded responses and the hypothetical conductance changes underlying them. Upper: responses
of typical insect muscle fiber to depolarizing pulse
of constant duration and progressively increasing
strength. Height of response increases progressively
but never comes to exceed stimulus height so response will propagate only decrementally. Lower:
hypothetical sodium and potassium conductances
changes to increasing stimulus strength. Sodium
current increases with each step, and so also does
potassium. Potential change does not reach sodium
equilibrium value.
gates away from the stimulated region. In
a maximally stimulated insect (Romalea)
muscle fiber a 30 mV response was reduced
to only 5 raV over 2.1 mm (Cerf et al.,
I960).
Where this type of responsiveness occurs,
information is changed in quality, from
digital partly to analogue form, and integration can occur in these membranes.
Graded responsiveness can only be utilized
though, when a relatively small area is to
be activated, close to the point of innervation. That is why it is necessary, with this
mechanism, to employ multi-terminal innervation. Why, in that case, complicate
the picture by graded electrical responses,
since presumably the primary post-synaptic
potentials could serve for the excitation
transfer as they do in frog slow skeletal
muscles and some crustacean muscles? It
is not yet possible to give a full answer to
this question, but it may be that the electrical response of an electrically excitable
membrane is the only method of ensuring
really quick subsequent activation of the
15
contractile machinery, in which case the
membrane would, in many muscles, need
to retain as much electric responsiveness as
was consistent with fine gradation of excitation at the membrane level.
It would, of course, be very satisfying if
we could explain graded electrical responsiveness, as well as other varieties of responsiveness, in terms of the general ionic model
by permitting some minor changes. One
way in which this can be done is to postulate that the potassium conductance change
rises much more steeply in this type of
membrane, other changes being of the
standard kind. This simple alteration gives
a surprisingly adequate account. If the potassium conductance rises almost as steeply
as the sodium conductance, then the membrane will not be able to depolarize to any
extent under the influence of increased sodium conductance before a rising potassium
conductance will cause potential changes in
the opposite direction. The rising voltage
will be cut off before there is time to swing
over to the sodium-equilibrium-potential
level. The process would be aided if sodium-inactivation also occurred either earlier or more readily.
The dependence of the magnitude of
the response on the magnitude of the depolarization, which is the essential feature
of gradedly-responsive-membrane, follows
from this hypothesis. The sodium current
is proportional to the depolarization in the
squid giant axon membrane, and likewise
in graded membrane. Thus the stronger
the stimulus the greater the extent of sodium activation and current flow. This
will lead to progressively greater responses,
but the potassium current will likewise increase progressively and so still cut off potential change before it swings over to the
sodium-equilibrium-potential value. The
graded responses have the shape of abortive spikes, never forming plateaus. This
strongly suggests a link between sodium inactivation and rising potassium current.
The proposed mechanism is illustrated in
Fig. 6. On this explanation very slight
changes in the timing of the conductance
changes, which might be expected to occur
naturally, would be reflected in relatively
16
G. HOYLE
large differences in the size and shape of
graded responses. Considerable variations
are usually encountered in successive graded
responses recorded from a fixed site.
So far, the validity of this proposed modification of the general ionic hypothesis has
not been subjected to rigorous testing, although there is substantial evidence in its
favor. One consequence of the proposal is
that it should be possible to make the normally graded membrane give all-or-nothing
responses. All that would be necessary
would be to impede potassium ion movement selectively. Even a slight increase in
membrane resistance might do this. In fact,
several arthropod muscle fibers have been
made to give propagated all-or-nothing responses simply by adding barium or strontium ions to the medium. (Fatt and Ginsborg, 1958; McCann et al., 1958; Werman
and Grundfest, 1958) These ions cause an
increase in membrane resistance. The potentials which result are greatly prolonged
compared with normal action potentials,
as would be expected if repolarization was
difficult owing to impeded potassium-ion
movement.
It would be nice to be able to achieve a
more normal-looking action potential than
the Sr/Ba one, perhaps by the action of a
drug applied in a minute dose. This has
recently been achieved in insects using the
mild insectide ryanodine (Fig. 8; Hoyle,
unpublished). Some minutes after the application of this drug to gradedly responsive locust muscle fibers, the fibers give allor-nothing spikes having a shape resembling that of normal action potentials of
nerve, or of ordinary vertebrate skeletal
muscle fibers. Even fibers which in normal
saline showed no sign of electrical responsiveness gave large spikes after ryanodine
treatment.
Alternative explanations for graded responsiveness have been offered, particularly
in terms of more thinly-distributed areas of
selective sodium-permeability increase (sodium "trap-doors"), compared with all-ornothing membrane. On this basis an increase in general electrical resistance might
be expected to bring about all-or-nothing
activity by carrying the initial excitation to
more trap-doors. However, in arthropod
muscle there are so many distributed nerve
endings that the surface membrane is
equally excited all over by each impulse;
therefore an increased resistance is not going to cause a greater spread than occurs
normally.
INHIBITION AND OTHER SYNAPTIC EVENTS
Inhibitory activity is often conducted to
the site of action by normal nerve impulses,
in which case it is a property of particular
synaptic sites. Chemical diffusion of inhibitory activity over a wide area also occurs, for example, in spreading "depression" in mammalian brains; but most inhibitory phenomena are highly local and
are not conducted except electrotonically.
That is, there is no evidence that inhibitory
changes are in any way regenerative, capable of exciting further inhibitory-type
response. The inhibitory change occurs
only in chemically excitable membrane. Although inhibitory phenomena are not
strictly within the scope of this article, it is
desirable to ask if it is possible to explain
inhibition in terms of the ionic theory.
Excitatory synaptic activity, too, must be
explicable in terms of the ionic hypothesis
for it to have full validity. A post-synaptic
potential rises rapidly and decays slowly;
often the decay is exponential, determined
by the purely electrical characteristics of
the membrane. (Fatt and Katz, 1951; Takeuchi and Takeuchi, I960). Synaptic-potential height is increased if the resting potential is artificially raised, and lowered if
it is reduced, in a linear manner (Fatt and
Katz, 1951; del Castillo et al., 1953). The
synaptic potential is associated with a temporary low resistance in the membrane region. Fatt and Katz explain it as a sudden
increase in the permeability of the subsynaptic membrane caused by the combination with it of transmitter substance. The
permeability change is certainly either a
general one, or to several ion species, not
just one kind of ion (del Castillo and Katz.
1954). This is analogous to the original
Bernstein explanation of the nerve impulse, as a non-specific increase in permeabilitv to all ions, and must lead to a de-
CONDUCTION IN NERVE AND MUSCLE
17
FIG. 8. Conversion of electrically-inexcitable membrane (muscle fiber of spiracular closing muscle,
Schistocerca) to all-or-nothing responsive membrane
by drug action (ryanodine, 10-"M). Muscle fiber re-
sjxmded to nerve stimulation only by post-synaptic
potentials before drug was applied. Under influence
of drug all-or-nothing spikes arise; local responses
when close to threshold.
polamation towards, but not beyond, 2ero
membrane potential. In fact post-synaptic
potentials never reach the zero level. The
resting nerve membrane in parallel with
the synaptic membrane discharges into the
depolarized synaptic region and gives a response if it is electrically excitable. Thus
excitatory synaptic activity is readily explicable in terms of the ionic theory.
Inhibitory activity is also associated with
a fall in membrane resistance, and is affected by membrane potential (Fatt and
Katz, 1953; Hutter and Trautwein, 1956;
Boistel and Fatt, 1958; Hoyle and Wiersma,
1958). Sometimes potential change is associated with inhibitory transmission, particularly when the membrane potential is
displaced above or below the normal resting level. This is always in the hyperpolarizing direction for membrane potentials at or below resting level, but quickly
becomes depolarizing when the membrane
is hyperpolarized. The potential at which
no change occurs is called the change-over
or reversal potential. Evidently the transmitter substance causes an increased permeability to an ion having an equilibrium
potential near to the normal resting poten-
18
G. HOYLE
tial. Inhibitory activity results in a displacement of the membrane potential towards this equilibrium potential. Either
chloride or potassium ions could fill this requirement, or both acting together. It seems
that either ion separately or both in concert
may be involved in inhibitory activity in
different situations. In crustacean muscle,
although it is by no means clear what actually causes the mechanical inhibition,
whether interference with ion flow or a
more direct action, the electrical potential
changes associated with it are probably due
to a selective increase in permeability to
chloride ions. In the sinus venosus of the
heart, where comparable hyperpolarizing
potentials appear, it seems also to be due to
chloride ions. But in the sensory terminals
of the stretch receptor of the crayfish, which
receive an inhibitory efferent innervation,
the inhibitory process appears to be due to
an increase in potassium-ion conductance
(Edwards and Hagiwara, 1959).
The inhibitory process in nerve cells and
in heart muscle has a similar basis in that
the functional aim in each case is to keep
the mean membrane potential high enough,
even in the face of continuing excitatory
disturbances, so that the level of potential
at which action potentials are set up is not
reached.
UPSIDE-DOWN ACTION POTENTIALS
The production of action potentials depends on the capacity of the membrane to
change state suddenly from one mode to
another and back again. The change in
state is not only produced by depolarizing
current, for starting with a nerve in the depolarized condition a comparable reaction
can be induced by hyperpolarizing current.
Segal (1958—squid giant axon) and Mueller
(1958—node of Ranvier) discovered independently that nerve cells depolarized by
potassium chloride react to hyperpolarizing
pulses of adequate strength not merely by
electrotonic changes but also by giving a
large response in the same direction. The
response is all-or-nothing and propagated,
i.e., it is an upside-down action potential.
In squid giant axon the upside-down action
potential is about 1000 times longer than
the normal one (Tasaki, 1959), but comparable reversed action potentials of crayfish
nerve fibers last for only five milliseconds.
In the latter preparation, long hyperpolarizing pulses give rise to repetitive responses
(Tomita et al., 1961).
On the ionic theory, raising the external
potassium ion concentration must cause depolarization, but only as long as the potassium conductance is high. Should the potassium conductance fall greatly relative to
the chloride conductance, then the chloride
ion will dominate. It seems that this is what
happens in the membrane. When it is hyperpolarized beyond a certain point it
jumps from a condition in which the potassium conductance is high, to one in which
it is low. In the depolarized membrane this
leads to a large potential shift towards the
chloride equilibrium potential value.
These findings have some consequences
for understanding the normal resting and
action potentials. Plots of resting potential
against external potassium concentration
show non-linearity at low potassium concentration ( = high membrane potential).
This is due to a great fall-off in potassium
conductance, coupled with the fact that it
is very difficult to reduce the external potassium value to zero. There is evidently
another external layer, separated by a small
space from the plasma membrane itself,
which acts as a barrier to the free diffusion
of ions. Diffusion of potassium out of this
space takes time, and there is constant replacement by potassium leaking out into it
from the cell (Harris and Sjodin, 1961).
Many excitable membranes do not behave as simple ohmic resistors (over a
range of potential change below the threshold for giving active responses) but show a
marked change in the slope of the voltagecurrent curve at a membrane potential
about equal to the resting potential (Yamasaki and Narahashi, 1959). Thereafter
outward, or depolarizing current passes
more readily, the membrane behaving like
a rectifier. This behavior is probably largely
concerned also with special behavior of the
potassium ion, which is a principal carrier
of current. It may be leaving as much as
two hundred times more readilv than it en-
CONDUCTION IN NERVE AND MUSCLE
ters. This behavior recalls that of semiconductors.
CONDUCTION IN SMOOTH MUSCLE
The foregoing accounts of conduction
processes are relevant to excitable cells in
general, but certain special problems arise
in regard to conduction in sheets of muscle
which are not clearly divided into discrete,
individually-innervated units. This includes
all the different kinds of smooth muscle
found in vertebrates, of the gut, ureter,
uterus, pupil, blood vessels, etc. and also
most of the muscles of invertebrates other
than arthropods. A characteristic feature
of all these very diverse muscles is that they
are composed of non-striated (smooth) cells
which are invariably thin, spindle-shaped,
uninucleate and, with one or two exceptions, short. Their fine innervation appears
to be by simple synaptic contacts (Caesar
et al., 1957; Richardson, 1958) but very
little is known about it.
The general innervation is probably
from a diffuse nerve net within the muscle
in most cases (Stohr, 1954; Boeke, 1949;
Hoyle, 1957). Conduction within the
muscle may thus occur in the nerve net, in
which case it is rather slow since at each of
the synapses within the net delay occurs.
Conduction in such nets may be apparently
decremental (Pantin, 1935), but this is
really due to a failure of the excitation to
pass certain synapses which require facilitation by successive impulses. There may be
through-conducting tracts in such nets,
either determined by yielding synapses or
special tracts of long fibers (Pantin, 1952)
and thus the appearance of a dual or multiple innervation may be created (Pople
and Ewer, 1954).
Three other kinds of conduction have
been proposed for various smooth muscles;
electrical, by the muscle fibers themselves;
by progressing stretch; and by diffusing
chemicals. Three possible mechanisms have
been suggested to explain the first of these
alternatives: 1, ephaptic transmission between overlapping cells; 2, low resistance
pathways between adjacent cells; 3, cytoplasmic continuity between cells. Regarding the latter, bridges have certainly been
19
located between smooth muscle cells (Prosser et al., I960) but these may be merely
structural rather than special electrical
pathways, although they undoubtedly facilitate electrical spread from one cell to another. All three alternatives must be regarded as possibilities.
All excitable cells are affected by being
stretched or relaxed and respond by membrane potential changes. In smooth muscle
the extent of depolarization associated with
stretch may be such as to lead to contraction
(Biilbring, 1955). This affords a simple mechanical means by which conduction may
occur in smooth muscles, since contraction
initiated at one end will stretch the adjacent cells and so on down the length.
Most smooth muscles are highly sensitive
to certain chemical agents (Rosenblueth,
1950) and this is the basis of general control of involuntary muscle by humoral
agents. Progressive diffusion is not, however, likely to be a major mode of conduction, but the influence of humoral agents is
neverthless very important in other ways.
Under their influence the excitability may
rise greatly. The cells will then become
more sensitive to stretch, and conduction by
this means may become possible. Also, individual cells will become much more susceptible to electrical stimulation by current
flowing from adjacent cells or groups of
cells (Burnstock and Prosser, 1960).
Thus there is probably no uniform pattern of conduction in smooth muscle. Not
only different modes but also different combinations of conduction modes are possible
arid different mechanisms may operate at
different times, depending on humoral influences, degree of stretch, etc.
The membranes of smooth muscle cells
probably differ in their properties just as
do those of striated muscle, being either
electrically unresponsive, gradedly responsive, or all-or-nothing; and of course they
may change according to local hormonal
conditions and stretch. The smooth muscle
cells of the vas deferens of the guinea-pig
can undoubtedly give all-or-nothing action
potentials (Burnstock and Holman, 1961).
The membrane potential is probably
mainly determined by the potassium-ion
20
G. HOYLE
distribution, but with a large chloride-ion
contribution. Sodium ions are probably
mainly responsible for the action potential
changes, but with a strong possibility of
other, unknown ions playing a significant
role (Holman, 1958).
ANOMALIES
A few anomalies have already been mentioned which are not easy to fit into the
general scheme of the ionic hypothesis.
There are others: for instance, artificial alteration of the internal concentration of potassium ions often does not have the predicted effect. Injection of potassium and
sodium into frog sartorius muscle fibers did
not affect the membrane potential (Falk
and Gerard, 1953). These experiments were
open to the objection that chloride, which
would reduce the membrane potential, was
injected at the same time. This objection
was met by introducing these salts, as well
as calcium and magnesium, along with aspartate and glutamate, into squid giant axons (Grundfest et al., 1954). However, no
significant changes of potential were obtained. In view of the success of Baker et
al., 1961) in replacing the extruded axoplasm by salt solutions, a procedure which
gave results according perfectly with the hypothesis, it can only be concluded that a
satisfactory injection of the salts cannot be
made with the axoplasm or myoplasm still
present.
Some years ago Tobias (1950) reported
that frog sartorius muscles soaked in distilled water until they had lost more than
99% of their potassium still developed a
resting potential as high as 40% normal.
Continuing this line of experiment, Stephenson (1957) soaked sartorius muscles in
potassium-free saline until the potassium
had fallen to one-third normal, and then
transferred them to saline containing potassium chloride. They accumulated an average of 31 mE/1 potassium in 50 min., but
the membrane potentials remained constant, although according to the ionic
theory they should have risen to 10 mV. In
this case the potassium measurements were
made on whole muscles and the resting po-
tential records were taken from outer fibers
which may have deteriorated.
Results more difficult to explain are provided by the demonstration that action potentials of unique shape may be developed
by some membranes in the complete absence of sodium but in the presence of substitute ions. Lorente de No et al. (1947) reported that, in frog nerves which had lost
the capacity to conduct by being soaked in
sodium-deficient media, certain small fibers
recovered their ability to conduct following
soaking in solutions containing certain quaternary ammonium compounds but no sodium. The majority of the nerve fibers, and
likewise frog ordinary skeletal muscle fibers
and crab axons, failed to recover responsiveness. Crustacean muscle fibers, however,
give larger responses than normally in completely sodium-free media, containing instead choline, tetraethylammonium or tetrabutylammonium (Fatt and Katz, 1953). Hydrazinium and hydroxylammonium ions,
though not perfect substitutes, at least paritally restore propagated responses in mammalian nerve fibers (Sugaya and Laget,
1958). Frog spinal ganglion cells (Koketsu
et al., 1959a) and insect muscle fibers
(Wood, 1958; Hoyle, unpublished) may be
added; and the list continues to grow.
In none of these cases is it possible to regard the quaternary ammonium compound
as a simple sodium substitute. Although
the height of the overshoot is proportional
to the concentration of the substitute ion,
in some cases a very small fraction suffices
to greatly prolong the action potential. In
the case of the larger ions, especially tetrabutyl ammonium, the action is irreversible
(crustacean muscle: Fatt and Katz, 1953).
In some insect muscles, several hours of
washing are required to restore a tetraethylammonium-treated muscle to normal. One
possibility raised by Fatt and Katz to explain their results in crustacean muscle was
that the action potential might be determined by the outward movement of internal anions, and this movement would be
facilitated by the external substitution of
the onium ions. Following their work on
the squid giant axon Tasaki and Hagiwara
(1957) thought that tetraethylammonium
CONDUCTION IN NERVE AND MUSCLE
might exert its influence only after penetrating the membrane to the inside of the
axon. It has no effect when added to the
bathing fluid but only when injected. In
confirmation of this possibility, typical, prolonged potentials are evoked by intracellular stimulation of frog spinal ganglion cells
following the injection of tetraethylammonium or hydrazine into the cells, although in that case they are effective when
applied externally also (Koketsu et al.,
1959a; Koketsu and Nishi, 1960). These responses occurred even when the cells were
bathed in medium containing no ions but
only sucrose (Koketsu et al., 19596). Evidently either some ions capable of carrying
current remain trapped outside the plasma
membrane but beneath some relatively impermeable sheath, or else an action potential mechanism supported entirely by the
outward movement of internal anions must
be postulated.
DISCUSSION
The experiments mentioned in the last
section remind us rather forcibly that the
ionic explanation of electrical activity in
nerve and muscle is still only a convenient
hypothesis. If any cellular mechanism were
discovered which could produce a resting
potential without recourse to concentration-cell effects, it would not be difficult to
bring the facts of ion distribution and
movement into line with it. At the same
time the anamolies are not so compelling
that we must abandon the hypothesis and
say "we simply do not know."
Tt has been shown that many of the most
significant variations in the shapes of action
potentials can probably be accounted for
quite satisfactorily on the basis of different
time-courses of permeability changes to various ion species. Some of the other phenomena, including action potentials in the
absence of external cations, can be explained if we postulate that outwardlyflowing anions can cany sufficient current
to give the observed changes. It does not
follow that this is the normal mechanism.
These ion changes probably do occur normally, but they are masked by the much
more massive inward movement of sodium
21
ions, or may even be inhibited by the sodium inflow.
It may be argued from this that it is the
structural changes in the membrane which
are the most significant ones in regard to
the functioning of excitable cells. The production of a resting potential is clearly important, but it is produced only in order
that it can be reduced by excitatory events
and thereby transduce and permit transmission of the stimulus. So far very little
attention has been paid to this problem of
the structural changes, although some attempts are now being made in this direction (Tobias, 1958; Tobias and Nelson,
1959). The Nachmanson group maintains
that the structural changes occurring in
electrically excitable membrane are analogous to those occurring in post-synaptic
membrane; i.e., they are the result of a combination between structural molecules of
the cell membrane and some active agent
released locally by depolarizing current
flow. This group, although maintaining
that this substance is in fact acetylcholine,
fails to explain why it is only at the synaptic regions that this drug can initiate action
potentials.
Apart from the structural transformations which must occur in association with
excitation, the principal physiological phenomenon providing a basis for excitability
and conduction must be the sodium pump
mechanism. At one time it was suggested
that the activity of the sodium pump might
be the direct cause of membrane potentials
(Grundfest, 1955) as it may well be in frog
skin (Ussing and Zerahn, 1951) but this
idea has been abandoned; it is unlikely
that the pump can produce more than a
few mV difference in potential especially if,
as is probable in nerve, it is a coupled
pump, taking in one potassium ion for each
sodium ion extruded. Unfortunately there
is no suitable molecular model for the
pump, or any other ion transport mechanism, although the way in which energy is
supplied to the pump is being discovered.
High-energy phosphate bonds generated by
metabolism are carried to the membrane as
arginine phosphate and ATP (Caklwell et
al., 1960r;). These in some way drive the so-
22
G.
high Na*
high CI"
low K +
External
medium
I coupled
\"Sut
T ci ;ut?
transfer/
Internal
medium
REST
HOYLE
A'CI"
An"
Na + .
in
high K+
high nondiffusible anion
low CI"
low No4
ACTIVITY
FIG. 9. Summary of principal ion movements determining activity in membrane. The clotted lines
in "inhibition" indicate permeability increases, not
RECOVERY
INHIBITION
necessarily resulting in any net movement in or out.
Passive ion movements occur at all times in addition.
dium pump, and arginine phosphate also ance appreciably delayed, the potential
maintains at the same time the potassium change goes far towards the sodium, equiuptake process which is coupled to sodium librium (reversal) potential and, since the
change is greater than the stimulus causing
extrusion (Caldwell et al., 19606).
In summary, there is overwhelming evi- it, it is regenerative and propogated in the
dence that the normal resting potential of form of an all-or-nothing impulse. The
nerve and muscle cells throughout the ani- final shape of this propagated disturbance
mal kingdom is the result of the inequality depends on the rate of change of the potasof distribution of ions across the mem- sium conductance change. The principal
brane. It is dominated by the potassium ion movements concerned in the electrical
ion, rarely by the chloride ion, and never activities of membranes are shown in Fig. 9.
by any other ion species. The inequality is
maintained by metabolically-driven ion
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