Lecture 18

Selectivity
Electrophysiology continued: V-gating
The speed of spike propagation and the
geometry of the axon
Role of myelination

Why are K+ channels highly selective for K+

and Na+ channels are not always highly
selective for Na+?
From the Goldman treatment we can see that
a sufficient depolarization can be easily
achieved with a non-selective cationic
channel that passes both Na+ and K+.
Indeed, we need to depolarize the membrane
to the threshold (- 55 mV) to evoke
excitation.
High selectivity for K+ is required specifically
to re-polarize the cell to its resting state (-70
mV) and keep it there.

Potassium channel KcsA (from Streptomyces lividans)

Selectivity filter
carbonyl oxygens
(red) substitute
for water and
provide high
selectivity for
potassium

In the selectivity filter of KcsA the K+ ion is overcoordinated

relative to bulk water where only four molecules constitute the
first hydration shell around the ion. Its because water forms
electrostatic H-bonds with the surrounding water which largely
outcompete the ion. In contrast, there are no H-binding groups
around the selectivity filter, which is dedicated to coordinate the
ion only.

from Varma and Rempe, BJ 2007

K+ ion can be coordinated by water (Hydroxyls), formamide

(Carbonyls) and by di-glycine (Bidentate carbonyl ligands). The latter
mimics the KcsA binding site and the computed free energy of transfer
from water to this biding site is close to zero. This is the condition for
the fastest transport in/out/across the channel.

from Varma and Rempe, BJ 2007

Carbonyl oxygens
cannot come in
touch with the
smaller Na+
because they start
repelling each other
(partial charge ~0.7e on each)

According to Molecular Dynamics, the

selectivity filter of KscA is not rigid,
but can easily collapse on a smaller
Na+ ion. However, the resultant
energy becomes higher due to
repulsion between the carbonyl
oxygens (see table on the next slide)

NMA = N-methylacetamide, a ligand that has carbonyls

From Noskov, Berneshe and Roux, Nature,2004

From Noskov, Berneshe and Roux, Nature,2004

The selectivity filter of L type Ca Channel consists of four Glutamic

acid sidechains (EEEE) crowded in a narrow space. Ions are
attracted or excluded based on the charge/volume ratio

Crowded with
Charge

+
++

Selectivity
Filter

O
E Side
Chains
Wolfgang Nonner, Robert Eisenberg

Selective Binding Curve: at approximately 10-6 M Ca2+

displaces Na+ in the selectivity filter L type Ca channel

L type Ca Channel

Wolfgang Nonner

Radial Crowding is Severe

In order to convert the channel from

Ca to Na-selective, the EEEE motif
can be changed to DEKA. All you
need is to put the charges into a 6
confinement
Ion Diameters
Pauling Diameters

Snap Shots of Contents

Ca++

1.98

Na+

2.00

K+

2.66

Side Chain Diameter

Lysine K

3.00

D or E

2.80

Channel Diameter 6

Side Chains are Spheres

Free to move inside channel

Parameters are Fixed in all calculations

in all solutions for all mutants
Experiments and Calculations done at pH 8
Boda, Nonner, Valisko, Henderson, Eisenberg & Gillespie

13

The Voltage Sensor

voltage-gated channel
o

electrometer

c
helices
S1-S6

Voltage dependence of open probability

Po
G / kT
ze / kT
e
e
Pc
Charged transmembrane helix = voltage sensor

Upward motion of voltage-sensor helices (S4)

Pc 1 Po

intrinsic bias

Po
e G / kT e ( Go ze ) / kT
Pc

o
c

Po
e ( Go ze ) / kT
1 Po

e ( Go ze ) / kT
1
Po
( Go ze ) / kT
( Go ze ) / kT
1 e
e
1

G 10kT
e 1.6022 10 19 C

k 1.381 10 23 J / K
T 310 K
z1 2

Po1( x)

z2 4

Po3( x) 0.4

0.8

0.6
Po2( x)

z3 10
Variations of the
charge in the sensor
change both the
midpoint and the
slope of activation
curves

0.2
0
0

0.05

0.1

, V

0.15

0.1

Po1( x)

0.01

Po2( x)
Po3( x)1 10 3

1 10

1 10

0.05

0.1

0.15

, V
A semi-log plot provides limiting slope for
Po at low potentials, which is proportional
to z

Typical z values for ion channels:

Shaker (delayed rectifier) z ~ 13 (3.25/subunit)
Various TRP channels z ~ 0.6-2
VDAC (mitochondrial anion channel) z~ 3-4

VDAC = voltage dependent anion channel, conducts ATP an

Scheme of VDAC gating under positive or
negative membrane potentials
positive lip

Modification of the gate by polyelectrolytes (dextran sulfate)

dramatically changes apparent z in VDAC

Properties of different fibers (axons) in the peripheral N

Fiber type Myelination
Conduction velocity

Function

Diameter

m/s

motoneurons

12-20

Touch sensation

5-12

30-70

muscle spindle

3-6

15-30

no

pain, temperature

visceral afferents,
1-3
auton. preganglion.

no

pain, temperature, 0.3-1.3 0.7-2.5

auton. postganglion.

2-5

70-120

12-30
3-15

What defines the speed of spike propagation?

unmyelinated fiber myelinated fiber

=regular wire

=High-frequency cable

K+

Na+

+30

-7 0

K+

Na+

V1

V2

C
R
V2

Charging time: = RC
(delay)

V1

time

r
R

Na+

Internal conductance is proportional to the cross-section:

G ~ r

R = 1/G, therefore R ~ 1/r2

Capacitance is proportional to the surface area of the cylinder A ~

therefore

C~r

Delay =RC is proportional to 1/r, therefore velocity V ~ r

Invertebrates

0.8 mm in diameter

2-5 micrometers

Vertebrates

Po intermembrane adhesion protein (immunoglobulin-like)

PMP22 helps compacting the membranes
MBP basic protein remaining in the cytosol
Gap junction proteins perforate membranes to allow nutrient

From Hille, 2001

Saltatory excitation in myelinated fibers

Fig. 8-17

Myelin coat reduces

CAPACITANCE

Velocity is proportional to the internodal distan

Fig. 8-13