Andrew Fielding Huxley
1917-2012
Sir Andrew Huxley (1917-2012) pioneered the physiology and biophysics of nerve conduction, skeletal muscle
activation and tension generation. His ground-breaking work on nerve excitability of nerve in collaboration with
Alan Hodgkin in the Cambridge Physiological Laboratory and the Plymouth Marine Biological Laboratory provided
the basis for our understanding of how voltage-gated ion channels generate propagating action potentials and
led to award of the 1963 Nobel Prize for Physiology and Medicine with Alan Hodgkin and Jack Eccles. Huxley
then went on to perform seminal work of similar importance on muscle activation and contraction whilst at
University College London. This led to the sliding filament theory and cross-bridge hypothesis of muscle
contraction, completing a momentous quest within physiology, in his view, “the mechanical engineering of living
things”.
Huxley was born in London within an illustrious family. His father Leonard was a writer and his grandfather
Thomas an early proponent of evolutionary theory. His half-brother Julian pioneered in animal behaviour and
Aldous, another half-brother, was a distinguished writer, authoring, among other books, Brave New World.
He was educated at University College (1925-30) and Westminster Schools (1930-5), winning a major
Entrance Scholarship in 1935 to Trinity College, Cambridge. His interests turned to physiology, for which his
studies pursued a medical direction including anatomy in 1937-8 and Part II Physiology in the Natural Sciences
Tripos (1938-9). He also showed exceptional engineering talent, which was to be his close companion for the
rest of his career, wherein he often invented equipment integral to his experiments. He thus invented a
micromanipulator, an interference microscope for studying striation patterns in muscle, and a microtome for
making electron microscope sections (Huxley, 1954, 1957a; Huxley & Niedergerke, 1958).
1
His first encounter with physiological research was in 1939 with Alan Hodgkin on the properties of the
propagated impulse in giant axons of squid. It was known that this was an all-or-none event resulting in an
advancing membrane potential change along the fibre cable structure thereby stimulating adjacent, initially
quiescent membrane. Bernstein (1902) had attributed the resting negativity of the fibre interior to a selective
permeability of the membrane to potassium relative to sodium, and the greater intracellular relative to
extracellular potassium concentration. The action potential might then result from a generalized increase in
membrane permeability to all ions in response to alteration of the internal potential beyond a threshold level,
collapsing this potential to zero. An increased membrane permeability had indeed been demonstrated by
membrane impedance measurements by a high-frequency alternating current (AC) bridge (Cole & Curtis, 1939).
However, Hodgkin and Huxley’s (1939, 1945) intracellular recordings of the action potential demonstrated that
the membrane potential becomes substantially positive (Fig. 1). This observation was to lead eventually to the
current view that this reflects an increased permeability specific for sodium ions, which would diffuse inwards
carrying a positive charge. However, work in this direction was interrupted by Hitler’s invasion of Poland and the
subsequent outbreak of war. It was only to resume seven years later, when Huxley returned from work first for
the British Anti-Aircraft Command and later for the Admiralty, developing radar control in antiaircraft guns and
naval gunnery.
Figure 1
Intracellular recording of the squid giant axon action potential.
A, photomicrograph of an electrode within a squid giant axon (diameter ~500 μm), showing two views of the same axon
which allowed simultaneous viewing of the electrode from both front and side made visible from a system of mirrors
devised by Huxley. This ensured that the electrode would not damage the nerve membrane as it was threaded down the
axon (Hodgkin & Huxley, 1945). B, the first intracellular recording of an action potential and its overshoot. The sine wave
time marker has a frequency of 500 Hz (Hodgkin & Huxley, 1939; by permission from Macmillan Publishers Ltd: Nature
C1939).
2
Andrew thus resumed his collaboration with Alan Hodgkin in 1946. By 1947, voltage clamp equipment invented
by Cole (Cole & Curtis, 1939; for a review see Cole, 1968) had successfully demonstrated continuous current–
voltage relationships in squid nerve membrane that nevertheless included a region of negative slope compatible
with the regenerative, all-or-none, property shown by the action potential. This was made possible through
control of the voltage through imposed steps from a chosen, resting level to known test values (‘voltage
clamping’) defined by the experimenter, as opposed to its variation through the complex time course of a
conducted action potential. It was then also possible to explore the time courses of sodium and potassium
currents traversing the membrane, and determine the underlying permeability changes, separated from the initial
capacitative charging current contributions, through different, controlled, test voltages (Fig. 2; Hodgkin et al.
1952). A consecutive sequence of four experimental papers described the current–voltage relationships in squid
giant axon membranes (Hodgkin et al. 1952), characterized their currents attributable to movements of sodium
and potassium ions (Hodgkin & Huxley, 1952a), and the effect upon these of varying the times and durations of
depolarizing and repolarizing steps (Hodgkin & Huxley, 1952b), and ended with studies on the ‘inactivation’ of
the sodium permeability following its initial activation produced by depolarization (Hodgkin & Huxley, 1952c).
Figure 2
A family of currents acquired using large depolarizing steps under voltage clamp control
Early records of this kind plotted both current traces with inward currents represented as positive and voltages with
depolarizations given relative to the holding potential and the outside voltage plotted relative to the inside. The –91 mV
step represents a depolarization of the inside of the nerve fibre to +15 mV (Hodgkin et al. 1952).
3
The final, theoretical paper then synthesized these results into a ‘Quantitative description of membrane current
and its application to conduction and excitation in nerve’ (Hodgkin & Huxley, 1952d), describing amongst the
most elegant applications of computational methods in the biological sciences. The sodium and potassium
conductances were described in terms of first order transitions with steeply voltage-dependent forward and
backward rate constants, with variables raised to their third (m3) and fourth (n4) powers, respectively, with the
sodium conductance additionally incorporating an inactivation (h) variable. The resulting reconstruction of the in
vivo conducted action potential closely agreed with the observed time courses and conduction velocities (Fig.
3a-d) (Hodgkin & Huxley, 1952d). It was also possible to reconstruct the detailed Na+ and K+ movements
through the action potential time course (Fig. 4). Thus was established the ionic hypothesis implicating
movements of sodium ions in the production and overshoot property of the in vivo action potential. An initial
stimulation or pre-existing activation of adjacent membrane would produce a rapid, steeply voltage-dependent
activation of the sodium conductance. This would result in a further depolarization, in turn further increasing
sodium permeability, initiating a positive feedback process terminated only as the membrane voltage approaches
the sodium Nernst potential, and with a slower potassium permeability activation driving a repolarizing outward
current. The latter would also contribute to membrane potential restoration to its resting level into a period of
refractoriness over which the sodium permeability and therefore the membrane regains its capacity for
activation (Historical accounts: Hodgkin, 1976; Huxley, 2002; Waxman & Vandenberg, 2012; Schwiening,
2012).
Figure 3
Computed (a and b) and experimentally recorded (c and d) action potentials propagated in squid giant axon at
18.5°C, plotted on fast and slow time scales.
Calculated conduction velocity was 18.8 m s-1; that actually observed was 21.2 m s-1 (Hodgkin & Huxley, 1952d).
4
Figure 4
Time courses of propagated action potential and underlying ionic conductance changes computed from voltage
clamp data.
The constants used corresponded to a 18.5°C temperature. Conduction velocity, 18.8 m s-1 (Hodgkin & Huxley, 1952d).
Over this time, Huxley also collaborated with Robert Stampfli on the function of the myelin sheath in vertebrate
nerve fibres in restricting inward and outward local current passage to the nodes of Ranvier, resulting in an
enhanced, salutatory, conduction of their nerve impulses between nodes (Lillie, 1925). This reflected the
reduced stimulation thresholds and greater sensitivity to anodal polarization and to local anaesthetics at nodal
than along internodal regions (Tasaki, 1953). Huxley and Stämpfli (1949) refined those earlier techniques,
pulling an isolated frog myelinated fibre through a short glass capillary traversing a partition separating two
Ringer-solution-filled compartments (Fig. 5A). The capillary diameter was small enough to impart the fluid-filled
space around the nerve an appreciable, 0.5 MΩ, resistance. Longitudinal current flow between neighbouring
nodes would then generate a measurable voltage across the two sides of the partition. The resulting records of
longitudinal current showed (Fig. 5B) that currents were similar in magnitude and timing at all points outside any
one internode but their peaks were displaced stepwise in time by ~0.1 ms as successive nodes were traversed.
The current flowing radially into or out of the fibre could be determined by subtracting successive pairs of
records from one another (Fig. 5C). This demonstrated only slight current leaks over the internodes but a brief
pulse of outward current followed by a much larger pulse of inward current restricted to each node.
5
Figure 5
Method used by Huxley and Stämpfli (1949) to investigate saltatory conduction.
A, the isolated frog nerve fibre was pulled through a 40 µm diameter aperture in an insulating partition. Current flowing
along the axis cyclinder out of one node and into the other indicated by the arrows causes a voltage drop outside the myelin
sheath. The 0.5 MΩ resistance of the fluid in the gap between the two pools permits measurement of the potential
difference between them. The internodal distance in a frog’s myelinated nerve fibre is about 2 mm. B, longitudinal currents
flowing at different positions along the fibre with the right hand diagram showing the position where each record was taken.
Distance between nodes ~2 mm. C, transverse currents at different positions along the fibre with each trace showing the
difference between successive longitudinal currents. Vertical mark above each trace shows the time at which membrane
potential change reached its peak at that position along the fibre. Outward current plotted upwards (Huxley & Stämpfli,
1949).
The 1963 Nobel Prize to Hodgkin and Huxley for their ionic hypothesis and Sir John Eccles for his work on
synaptic signalling thus recognized key contributions that provided the conceptual foundation for studies of
excitable cell signalling. They had a similar significance for neurophysiology and biophysics as the structure of
DNA reported by Watson and Crick had for biochemistry. The findings in nerve prompted a cascade of important
discoveries whose implications range from the fundamentals of channel function, through their application to
excitable tissues generally, to their translation to understanding the basic mechanisms of disease. Firstly, of
6
those concerning sodium channel properties and function itself, the voltage dependence of the sodium
conductance and its rate constants led Hodgkin and Huxley to predict that channel opening and closing would
involve net transfers of intramembrane charge in response to alterations in the transmembrane electric field.
Such gating currents were to be demonstrated twenty years later, providing a direct biophysical handle for
studying the mechanisms of the molecular configurational changes underlying channel activation (Armstrong &
Bezanilla, 1973; Keynes & Rojas, 1974). The 1991 Nobel Prize was then to be awarded to Erwin Neher and Bert
Sakmann for their introduction of the patch clamp technique. This made direct measurements of currents
traversing single sodium channels, thereby directly demonstrating the unit channel events through single ionic
channels underlying the observed conductances (Sakmann & Neher, 1983, 1984; Hamill et al. 1981; Raju, 2000;
Nilius, 2003). Finally, in more recent years, the field of biochemistry was to describe the structure of the sodium
channel and characterize its gating transitions (Yarov-Yarovy et al. 2011; Payandeh et al. 2012).
Secondly, both the voltage clamp techniques and their associated mathematical formulations were applicable to
analysis of function in other excitable tissues, including mammalian nerve (Huxley & Stampfli, 1949;
Frankenhaeuser & Huxley, 1964), skeletal (Adrian et al. 1970) and cardiac muscle (Noble, 1962, 1984), and in
neuronal encoding processes exemplified by repetitively firing gastropod nerve (Connor & Stevens, 1971a-c).
Thirdly, the electrical circuit theory formulations used in the ionic hypothesis prompted subsequent more realistic
mathematical simulations that could reconstruct not only electrophysiological, but also volume regulatory
effects, of not only electrogenic, but also of electroneutral and osmotic fluxes and metabolic change (Fraser &
Huang, 2004; Fraser et al. 2005; Usher-Smith et al. 2006).
Finally, the fundamental ideas indicated paths through which work seeking translational implications for clinical
medicine would follow. Within nerve function these concerned our fundamental understanding of local
anaesthesia and pain, as well as of the importance of the Schwann cell sheath on conduction velocity in
demyelinating conditions. Skeletal muscle proved a fertile ground for the application of both the Hodgkin-Huxley
analysis and cable theory in an analysis of the repetitive firing in the neurological condition of myotonia congenita
(Adrian & Bryant, 1974). Arrhythmic and abnormal excitation conditions in cardiac muscle have proven an
important area for the application of basic biophysical ideas (Lei et al. 2008). These included recent studies of
genetically modified murine cardiac models for sodium channelopathies (Papadatos et al. 2002; Sabir et al.
2008; Killeen et al. 2008). These demonstrated how altered sodium channel activation and recovery properties
would result in sino-atrial pacemaker (Lei et al. 2005), atrial and ventricular arrhythmic disorders, in murine
models for the human arrhythmogenic conditions including the Brugada and Long QT3 syndromes (Martin et al.
2011, 2012; Matthews et al. 2012).
7
Huxley moved from Cambridge to University College London in 1960, turning his interests to skeletal muscle,
starting with the recognition that the excitation beginning in its surface membrane need to be transduced into a
contractile activation of myofilaments in the fibre interior. AV Hill (1948; for a full historical account see Hill,
1965) had demonstrated that the timescale of such excitation was difficult to explain in terms of diffusion into
the interior of an activating substance liberated at the surface membrane. However, preliminary light microscope
evidence suggested a “Krause’s membrane” that might form a continuous structure across the fibre at the Z-line.
Huxley and Taylor (1958) depolarized very small patches of the surface membrane of isolated muscle fibres by
placing the end of a ~1 μm diameter micropipette in contact with the surface and applying a negative electric
potential to the fluid contained within the pipette. They demonstrated a highly localised contraction, visible
under interference microscopy, only when the pipette apposed an I band, and never when the pipette was
opposite an A band (Fig. 6). A loose-patch adaptation of this localized micropipette technique was to prove
useful to characterize channel distributions over the membrane area (Almers et al. 1983). Electron microscopic
studies correlated this with an occurrence of a transverse tubular membrane system continuous with the surface
membrane and open to the extracellular space (Huxley & Taylor, 1958; Huxley, 1982). The latter structure,
including its fragility following osmotically induced volume change (Gage & Eisenberg, 1969; Fraser et al. 1998),
was to be the subject of subsequent study by, among others, Clara Franzini-Armstrong, Robert Eisenberg and
Lee Peachey, who had begun scientific work with Huxley. These prompted the application of electrical cable
representations of that tubular geometry to Hodgkin & Huxley’s original analysis, in a reconstruction of its role in
active conduction of excitation into the fibre interior and the activation of contraction (Adrian & Peachey, 1973;
Huang & Peachey, 1992). This, in turn, led to the current view suggesting a rapid propagation of the action
potential along the membrane surface to the ends of the fibre. The lower frequency components of this action
potential then activate the tubules by initiating a further centripetal wave of excitable activity (Sheikh et al.
2001; Pedersen et al. 2011). Finally, clarifications of the subsequent excitation–contraction coupling
mechanisms at the molecular level, involving dihydropyridine receptor-mediated voltage sensing allosterically
coupled to ryanodine receptor-mediated release of intracellularly stored calcium, similarly involved voltage clamp
techniques (Huang, 1988, 1993; Huang et al. 2011; Huang & Peachey, 1989, 1992).
8
Figure 6
Local activation experiments in amphibian skeletal muscle.
Panels 1-4 show the edge of an isolated frog muscle fibre with apposed pipette. This is photographed under polarized light
with A bands appearing dark. Comparison of the results of stimulation at an A (panels 1 and 2) and an I band (panels 3 and
4) before (panel 1 and 3) and during (panels 2 and 4) stimulation demonstrates contraction only with the pipette opposite
an I band (panel 4). Successive cine frames (at 16 frames s–1; panels 5-8) show the shortening where the local
depolarization is applied between panels 5 and 6 (Huxley & Taylor, 1958).
9
Huxley’s interest then turned to muscle contraction itself. It had previously been assumed that muscle
contraction involved coiling and contraction of long protein molecules akin to the shortening of a helical spring.
Andrew Huxley & Rolf Niedergerke, and Hugh Huxley & Jean Hanson, independently suggested the sliding
filament theory (Huxley & Niedergerke, 1954; Huxley & Hanson, 1954), prompted by findings that sarcomeric A
band lengths remained constant in both stretched and actively or passively shortening muscle. Huxley then
produced elegant evidence that contraction thus resulted from a relative sliding of thin filaments between thick
filaments probably driven by cross bridge interactions between them (Gordon et al. 1966). This compared
isometric tension and filament overlap itself held at a range of fixed lengths by optical servomechanisms in single
amphibian muscle fibres. The resulting length–tension diagram (Fig. 7A) closely correlated with predictions from
electronmicroscopy determinations (Fig. 7B) of 2.05 µm long actin, including a 0.05 µm Z-line, and 1.6 µm long
myosin, filaments whose 0.15 to 0.2 µm middle regions were bare of cross bridges. Thus, (1) sarcomere lengths
>3.65 µm would not permit cross bridge formation directly explaining the accompanying loss of tension
development (Fig. 7C). In contrast, between 3.65 µm and (2) 2.2 to 2.25 µm, cross bridge number would
linearly increase with decreasing sarcomere length. This correlated with the corresponding linear increase in
isometric tension. However, further shortening between (2) and (3) would leave constant cross bridge numbers,
predicting the tension plateau between 2.05 and 2.2 µm. Tension fell with further shortening beyond (3)
attributable to actin filament overlap. (4) Below ~2.0 µm a clash between actin filaments between halves of the
sarcomere would predict the fall in tension. (5) At 1.65 µm, myosin filaments would hit the Z line, predicting a
distinct kink in the curve beyond which tension falls much more sharply to zero tension at ~1.3 µm before (6).
10
Figure 7
Analysis of the length–tension relationship of skeletal muscle in terms of a cross bridge hypothesis.
A, the isometric tension of isolated frog muscle fibre at different sarcomere lengths. The numbers 1 to 6 refer to the
myofilament positions shown in C. B, electronmicroscopic measurements of myofilament dimensions in frog muscle. C,
myofilament arrangements at different lengths. Letters a, b, c and z refer to dimensions given in panel A (Gordon et al.
1966).
Huxley’s final interest concerned the cross bridge interactions mediating the cross bridge sliding itself
accompanied by ATP breakdown (Huxley, 1957b). Cytsolic Ca2+ elevation then initiates cyclic reactions between
projections on the myosin filaments and active sites on the actin filaments in the form of cross bridge formation
and configurational change that drives a filament sliding and ATP breakdown. Huxley’s 1974 model (Huxley &
Simmons, 1971; Huxley, 1974) explained the resulting tension transients in terms of elastic and step-wise
shortening elements driven by an actin-myosin binding through a sequence of attachment sites each reflecting
increasing strengths of interaction (1 to 3 in Fig. 8), Myosin detachment, permitting re-initiation of a further
11
cross bridge cycle with a fresh actin binding site, would then take place in position 3 accompanied by ATP
hydrolysis. This final direction of work involved amongst others, Lincoln Ford, Yale Goldman, Hugo GonzalezSerratos, Lucy Brown, Vincenzo Lombardi and Gabriella Piazzesi.
Figure 8
The Huxley-Simmons (1971) model for cross bridge interaction.
This incorporates elastic and step-wise shortening elements and three possible myosin head positions 1, 2 and 3 of
successively greater strengths of binding to actin. The myosin head can dissociate in position 1 without, but in position 3
only with ATP utilization (Huxley, 1974).
12
Sir Andrew was elected to the Royal Society in 1955 and was its President between 1980 and 1985. He
became Jodrell Professor of Physiology in 1960, then Royal Society Research Professor in University College
London in 1969. He was Master of Trinity College, Cambridge between 1984 and 1990, knighted in 1974 and
appointed Order of Merit in 1983. He was elected Ordinary and Honorary Member of the Physiological Society
in 1942 and 1979, served in its Committee (1957-61; 1970-4) and served on the Editorial Board of The
Journal of Physiology (1950-57). He was joint president of the International Union of Physiological Societies in
1986 to 1993. He worked at Woods Hole, Massachusetts, in 1953 as a Lalor Scholar, and gave the Herter
Lectures at Johns Hopkins Medical School (1959) and the Jesup Lectures at Columbia University (1964). In
1947 Andrew Huxley married Jocelyn Richenda Gammell Pease, daughter of the geneticist M. S. Pease, and the
Hon. H. B. Pease (née Wedgwood), who predeceased him in 2003. They had five daughters and a son.
Acknowledgements
I would like to record my deep gratitude to Andrew Huxley for his encouragement of work I pursued on surface
and tubular action potential conduction in skeletal muscle, channelopathic models for arrhythmogenesis in
cardiac muscle, and with Lee Peachey and the late Richard Adrian on excitation-contraction coupling, during
which Lee Peachey stayed with Huxley in the Trinity College Master’s Lodge. I thank Carol Huxley for important
biographical details, Jeremy Skepper and Alan Catell for archival information, particularly concerning
instrumentation invented by Huxley. I apologize in advance to those whose contributions and roles in Sir
Andrew’s life I may have inadvertently omitted or slighted.
Christopher L-H Huang
Professor of Cell Physiology, University of Cambridge
13
References
Adrian RH & Bryant SH (1974). On the repetitive discharge in myotonic muscle fibres. J Physiol 240, 505-515.
Adrian RH & Peachey LD (1973). Reconstruction of the action potential of frog sartorius muscle. J Physiol 235, 103-131.
Adrian RH, Chandler WK & Hodgkin AL (1970). Voltage clamp experiments in striated muscle fibres. J Physiol 208, 607644.
Almers W, Stanfield PR & Stühmer W (1983). Lateral distribution of sodium and potassium channels in frog skeletal muscle:
measurements with a patch-clamp Technique. J Physiol 336, 261-284.
Armstrong CM, Bezanilla F (1973). Currents related to movement of the gating particles of the sodium channels. Nature
242, 459-461.
Bernstein J (1902). Untersuchungen zur Thermodynamik der bioelektrischen Ströme. Pflügers Archiv 92, 521–562.
Cole KS & Curtis HJ (1939). Electric impedance of the squid giant axon during activity. J Gen Physiol 22, 649–670.
Cole KS (1968). Membranes, Ions and Impulses. University of California Press, Berkeley.
Connor JA & Stevens CF (1971a). Inward and delayed outward membrane currents in isolated neural somata under voltage
clamp. J Physiol 213, 1-19.
Connor JA & Stevens CF (1971b). Voltage clamp studies of a transient outward membrane current in gastropod neural
somata. J Physiol 213, 21-30.
Connor JA & Stevens CF (1971c). Prediction of repetitive firing behaviour from voltage clamp data on an isolated neurone
soma. J Physiol 213, 31-53.
Frankenhaeuser B & Huxley AF (1964). Action potential in myelinated nerve fibre of Xenopus laevis as computed on basis of
voltage clamp data. J Physiol 171, 302–315.
Fraser JA & Huang CLH (2004). A quantitative analysis of cell volume and resting potential determination and regulation in
excitable cells. J Physiol 559, 459-478.
Fraser JA, Middlebrook CE, Usher-Smith JA, Schwiening CJ & Huang CL-H (2005). The effect of intracellular acidification on
the relationship between cell volume and membrane potential in amphibian skeletal muscle. J Physiol 563, 745-64.
Fraser JA, Skepper JN, Hockaday AR & Huang CLH (1998). The tubular vacuolation process in amphibian skeletal muscle. J
Muscle Res Cell Motil 19, 613-629.
14
Gage PW & Eisenberg RS (1969). Action potentials, afterpotentials, and excitation-contraction coupling in frog sartorius
fibers without transverse tubules. J Gen Physiol 53, 298-310.
Gordon AM, Huxley AF & Julian FJ (1966). The variation in isometric tension with sarcomere length in vertebrate muscle
fibres. J Physiol 184, 170-192.
Hamill OP, Marty A, Neher E, Sakmann B & Sigworth FJ (1981). Improved patch-clamp techniques for high-resolution
current recording from cells and cell-free membrane patches. Pflugers Arch 391, 85-100.
Hill AV (1948). On the time required for diffusion and its relation to proceeses in muscle. Proc R Soc B 135, 446-53.
Hill AV (1965). Trails and trials in physiology. London: Edward Arnold. On the time required for diffusion and its relation to
proceeses in muscle. Proc R Soc B 135, 446-53.
Hodgkin AL & Huxley AF (1939). Action potentials recorded from inside a nerve fibre. Nature 144, 710-711.
Hodgkin AL & Huxley AF (1945). Resting and action potentials in single nerve fibres. J Physiol 104, 176-195.
Hodgkin AL & Huxley AF (1952a). Currents carried by sodium and potassium ions through the membrane of the giant axon
of Loligo. J Physiol 116, 449-472.
Hodgkin AL & Huxley AF (1952b). The components of membrane conductance in the giant axon of Loligo. J Physiol 116,
473-496.
Hodgkin AL & Huxley AF (1952c). The dual effect of membrane potential on sodium conductance in the giant axon of
Loligo. J Physiol 116, 497-506.
Hodgkin AL & Huxley AF (1952d). Aquantitative description of membrane current and its application to conduction and
excitation in nerve. J Physiol 117, 500–44.
Hodgkin AL (1976). Chance and design in electrophysiology – informal account of certain experiments on nerve carried out
between 1934 and 1952. J Physiol 263, 1–21.
Hodgkin AL, Huxley AF & Katz B (1952). Measurement of current voltage relations in the membrane of the giant axon of
Loligo. J Physiol 116, 424–48.
Huang CLH & Peachey LD (1989). Anatomical distribution of voltage-dependent membrane capacitance in frog skeletal
muscle fibers. J Gen Physiol 93, 565-584.
Huang CLH & Peachey LD (1992). A reconstruction of charge movement during the action potential in frog skeletal muscle.
Biophys J 61, 1133-1146.
15
Huang CL-H (1988). Intramembrane charge movements in skeletal muscle. Physiol Rev 68, 1197-1147.
Huang CLH, Pedersen TH & Fraser JA (2011). Reciprocal dihydropyridine and ryanodine receptor interactions in skeletal
muscle activation. J Muscle Res Cell Motil 32, 171-202.
Huang CLH (1993). Intramembrane Charge Movements in Striated Muscle. Monographs of the Physiological Society, No.
44. Clarendon Press, Oxford.
Huxley A (1982). The Florey Lecture, 1982. Discovery: accident or design? Proc R Soc Lond B Biol Sci 216, 253-266.
Huxley AF & Niedergerke R (1954). Structural changes in muscle during contraction. Interference microscopy of living
muscle fibres. Nature 173, 971–973.
Huxley AF & Niedergerke R (1958). Measurement of the striations of isolated muscle fibres with the interference
microscope. J Physiol 144, 403-425.
Huxley AF & Simmons RM (1971). Proposed mechanism of force generation in striated muscle. Nature 233, 533-538.
Huxley AF & Stampfi R (1949). Evidence for saltatory conduction in peripheral myelinated nerve fibres. J Physiol 108, 315339
Huxley AF & Taylor RE (1958). Local activation of striated muscle fibres. J Physiol 144, 426-441.
Huxley AF (1954). A high-power interference microscope. J Physiol 125, 11-13P.
Huxley AF (1957a). An ultramicrotome. J Physiol 137, 73-74P.
Huxley AF (1957b). Muscle structure and theories of contraction. Prog Biophys Biophys Chem 7, 255-318.
Huxley AF (1974). Muscular contraction. J Physiol 243, 1-43.
Huxley AF (2002). Hodgkin and the action potential 1935–1952. J Physiol 538, 2.
Huxley HE & Hanson J (1954). Change in the cross-striations of muscle during contraction and stretch and their structural
interpretation. Nature 173, 973–976.
Keynes RD & Rojas E (1974). Kinetics and steady-state properties of the charged system controlling sodium conductance
in the squid giant axon. J Physiol 239, 393-434.
Killeen MJ, Sabir IN, Grace AA & Huang CLH (2008). Dispersions of repolarization and ventricular arrhythmogenesis: lessons
from animal models. Prog Biophys Mol Biol 98, 219-229.
16
Lei M, Goddard C, Liu J, Léoni AL, Royer A, Fung SS, Xiao G, Ma A, Zhang H, Charpentier F, Vandenberg JI, Colledge WH,
Grace AA & Huang CLH (2005). Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel
gene Scn5a. J Physiol 567, 387-400.
Lei M, Grace AA & Huang CLH (Eds) (2008). Double focus issue: Translational models for cardiac arrhythmogenesis. Prog
Biophys Mol Biol Vol. 98.
Lillie RS (1925). Factors affecting tansmosion and recovery in the passive iron nerve model. J Gen Physiol 7, 473-507.
Martin CA, Huang CLH & Matthews GD (2011). Recent developments in the management of patients at risk for sudden
cardiac death. Postgrad Med 123, 84-94.
Martin CA., Siedlecka U, Kemmerich K, Lawrence J, Cartledge J, Guzadhur L, Brice N, Grace AA, Schwiening C, Terracciano
CM & Huang CLH (2012). Reduced Na+ and higher K+ channel expression and function contribute to right ventricular origin
of arrhythmias in Scn5a+/- mice. Open Biol 2, 120072.
Matthews GD, Guzadhur L, Grace A & Huang CLH (2012). Nonlinearity between action potential alternans and restitution,
which both predict ventricular arrhythmic properties in Scn5a+/- and wild-type murine hearts. J Appl Physiol 112, 18471863.
Nilius B (2003). Pflügers Archiv and the advent of modern electrophysiology. From the first action potential to patch clamp.
Pflugers Arch 447, 267-271.
Noble D (1962). Modification of Hodgkin-Huxley equations applicable to purkinje fibre action and purkinje fibre pacemaker
potentials. J Physiol 160, 317-352.
Noble D (1984). The Initiation of the Heartbeat. 3rd edn. Oxford University Press.
Papadatos GA, Wallerstein PM, Head CE, Ratcliff R, Brady PA, Benndorf K, Saumarez RC, Trezise AE, Huang CLH,
Vandenberg JI, Colledge WH & Grace AA (2002). Slowed conduction and ventricular tachycardia after targeted disruption
of the cardiac Sodium channel gene Scn5a. Proc Natl Acad Sci U S A 99, 6210-6215.
Payandeh J, Gamal El-Din TM, Scheuer T, Zheng N & Catterall WA (2012). Crystal structure of a voltage-gated sodium
channel in two potentially inactivated states. Nature 486, 135-139.
Pedersen TH, Huang CLH & Fraser JA (2011). An analysis of the relationships between subthreshold electrical properties
and excitability in skeletal muscle. J Gen Physiol 138, 73-93.
Raju TN (2000). The Nobel chronicles. 1991 Erwin Neher (b 1944) and Bert Sakman (b 1942). Lancet 355, 1732.
Sabir IN, Killeen MJ, Grace AA & Huang CLH (2008). Ventricular arrhythmogenesis: insights from murine models. Prog
Biophys Mol Biol 98, 208-218.
17
Sakmann B & Neher E (1983). Single Channel Recording. Plenum Press, NY.
Sakmann B & Neher E (1984). Patch clamp techniques for studying ionic channels in excitable membranes. Annu Rev Physiol
46, 455-472.
Schwiening CJ (2012). A brief historical perspective: Hodgkin and Huxley. J Physiol 590, 2571-2575.
Sheikh SM, Skepper JN, Chawla S, Vandenberg JI, Elneil S & Huang CLH (2001). Normal conduction of surface action
potentials in detubulated amphibian skeletal muscle fibres. J Physiol 535, 579-590.
Tasaki I (1953). Nervous transmission. Charles C Thomas, Springfield.
Usher-Smith JA, Fraser JA, Bailey PS, Griffin JL & Huang CL-H (2006). The influence of intracellular lactate and H+ on cell
volume in amphibian skeletal muscle. J Physiol 573, 799-818.
Waxman SG & Vandenberg JI (2012). Hodgkin and Huxley and the basis for electrical signalling: a remarkable legacy still
going strong. J Physiol 590, 2569-2570.
Yarov-Yarovoy V, DeCaen PG, Westenbroek RE, Pan CY, Scheuer T, Baker D & Catterall WA (2011). Structural basis for
gating charge movement in the voltage sensor of a sodium channel. Proc Natl Acad Sci U S A 109, 93-102.
18