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Presentation Bio502 Hodgkin Huxley Neuron 3 13 17 2
Presentation Bio502 Hodgkin Huxley Neuron 3 13 17 2
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
*fenestrations that
allow small,
hydrophobic
physiological regulators
and pore-blocking drugs
to bind to receptor site
(local anesthetic,
antiarrhythmic, and
antiepileptic drugs)
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
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.