The Hodgkin-Huxley Heritage:

From Channels To Circuits,

A Symposium Review
Catterall et al., 2012
Presented by Matt London

Hodgkin Huxley
1952: Landmark series of experiments by Hodgkin and Huxley
using voltage-clamp technique on squid giant axon
 Discovered action potential initiated by Na+ current
Predicted shape of neuron action potential
Beyond Action Potential Model
Conceptual Basis for 3 Levels of Research in Neuroscience
1. Molecular
Structural and Functional Properties of ion channels:
Ion Permeation, Selectivity, Gating

2. Cellular
Onset Timing of Action Potential:
Threshold and Refractory Periods

3. Circuit
Computational Neuroscience
1980-2000: Extensive structure-function studies of action potential
Na+ channels identified and purified in active form from mammalian brain using neurotoxins as
molecular probes
Primary Structures of Subunits of Mammalian Voltage-Gated Na+ Channels
2 functional modules: voltage-sensing module (S1-S4 segments), pore-forming module (S5 and S6)
subunit
260 kDa
subunit whitewhite circles=outer
circles=outer and innerandringsinner rings
of amino of amino
residues that
form residues
ion thatfilter
selectivity form ion
and selectivity
tetrodotoxin filter site
binding
30-40 kDa N-linked glycosylation
Domains I II III IV

Voltage-dependent
activation of channel
depends on gating
charges located in S4
segments

cylinders=alpha-helical
segments
yellow=S4 voltage sensors
Payandeh et al. (2011) uses x-ray crystallographic to study ancestral bacterial Na+ channel
NavAb in Arcobacter buzleri pore has wide outer vestibule
and narrow intracellular
activation gate in closed
conformation

water-filled selectivity filter

with four acidic side-chains
surrounding narrowest part
of ion conduction pathway
 Unanticipated Discoveries*

*fenestrations that
allow small,
hydrophobic
physiological regulators
and pore-blocking drugs
to bind to receptor site
(local anesthetic,
antiarrhythmic, and
antiepileptic drugs)

*arginine gating charges, at intervals of 3 aa residues

in the S4 segments make multiple hydrophilic
interactions within voltage sensor of NavAb, including
H bonds to protein backbone carbonyls

slow-inactivation (prolonged depolarization) of Na+

channels has conformational change that increases
affinity for drug binding to inactivated state of Na+
channels

ENC=extracellular negative clusters

HCS=hydrophobic constriction site
 Mechanisms of Na+ Channel Activation and Inactivation
Work in the 1980's confirmed Hodgkin and Huxley's inactivation model:
physical correlate of inactivation h-gate is linker between domains III and IV

S4 segments are voltage sensors that initiate fast-activation

fast

mediated by
gate (blue
circles);
connects
domains III
and IV
inactivation particle, isoleucine-phenylalanine-
methionine-threonine, in gate folds into pore
and blocks it
Fast inactivation by a single gate, structurally contained in -subunit, defines sodium currents in squid giant
axon as well as in nerve, muscle, and endocrine cells from invertebrates to mammals
 Voltage-Gated K+ Channel

Slow-activation
positively charged amino acid residues of S4
interact with negative charges on S1-S3
positive charges jump from one negative
charge to the next, causing conformational
change in VSD
S4-S5 linker is displaced, opening pore

Slow-inactivation by ammonium ions

 Hodgkin-Huxley Model of Neuron Excitability
total membrane current (Itotal) crosses zero at two points
Itotal = the sum of the steady-state current (INA) and resting-conductance potassium and leak
currents (IK + Ileak)
A (resting potential)
B (threshold)

Hodgkin-Huxley formula: Itotal = Kn4(65)[V EK] + Nam3(V)h(V)[V ENa] + gleak[V Eleak)

If membrane potential is perturbed only a little from rest, direction of membrane current is attracted back to A
If it exceeds unstable fixed point B, then membrane potential has positive derivative, driving it further away
from B, and an action potential is generated
Applications of Hodgkin and Huxley Theory to Spike Generation and Timing in Cortical Neurons
2 different classes of regularly spiking nerve fiber (Hodgkin and Huxley used crab nerve)
V = membrane potential, W = potassium activation or recovery variable
inset: voltage vs. time responses (spike are curtailed)
red circle: coalesced fixed points at threshold

preferentially respond to oscillating input

less easily led astray into long pauses by small
stable low-frequency firing fluctuations and are better-suited to spike time
effective at encoding different levels of input into a encoding than Class 1 neurons
continuous range of firing rates fast-spiking inhibitory behave in Class 2 manner
regular-spiking excitatory cells (i.e. layer 2/3
pyramidal cells and some layer 5 pyramidal cells) and
nonpyramidal regular-spiking inhibitory interneurons
behave in Class 1 manner

near-threshold response of a fast-spiking inhibitory

interneuron switches between spiking at the threshold
stable low-frequency firing in nonpyramidal regular-spiking frequency and subthreshold oscillations
interneuron
 Hodgkin-Huxley Models In Computational Neuroscience
current digital computers can simulate thousands of Hodgkin-Huxley model neurons
ion channel efficiency in generating action potentials
human brain uses >2x glucose per day as the heart
action potentials, dendritic integration, and synaptic transmission account for more than half this energy
use
single thin spikes are more energetically expensive than single thick spikes and the cost of a fast-spike train is minimized
with fast Na+ inactivation

slow potassium activation

superimposed on resulting
sodium (orange) and
potassium (purple) currents
and total # of transferred
ions (blue) fast potassium activation
has thinner width and
larger # of transferred ions

Na inactivation time constant (msec)

energy cost of Hodgkin-

Huxley model with fast
spiking is minimized when
Na+ inactivation speed is
matched to K+ activation
speed
 Discussion
The Hodgkin and Huxley studies from 60 years ago set the framework modern neuroscience research
structural and functional properties of ion channels, theorized by Hodgkin and Huxley, have been identified and
investigated, with focus on mechanisms of ion permeation, selectivity, and gating
cellular level model used in investigations of rate and timing of action potentials, essential for neural encoding of
information
studies of neuronal integration and circuit level processing have utilized Hodgkin-Huxley formalism to investigate
how nervous system evolved to minimize energy cost
The Hodgkin-Huxley model of the action potential continues to produce new insights into the properties of
neurons and neural circuits, which empower brains with powerful computational capacities that we are just
beginning to understand

Critique
insufficient info re: activation of Na+ and K+ channels
insufficient info overall re: K+ channels
many instances of unclear distinction between ideas of Hodgkin and Huxley and ideas of following scientists
what was discussed of Na+ ion channel structure and inactivation was very in-depth; the best part of article
Catterall WA, Raman IM, Robinson HP, Sejnowski TJ, Paulsen O. 2012. The Hodgkin-Huxley Heritage:
From Channels To Circuits. J Neurosci 32(41):14064-73.