Electrical Signals I

Electrical Signals I
Page 1


Wonder of electrical signals
Ion channelsmagic behind electrical signals
Permeation of ion channels

9/05/2012 & 9/10/2012

Page 2

1. What are excitable membranes and why are they exciting?

One of the most ubiquitous forms of communication in biology utilizes the modality of changes in
membrane potential, or electrical signaling. Excitable membranes are those which possess the
intrinsic capability of generating such electrical signals. Their stereotypic electrical response is
called an action potential.

The long sought after and key biological signal turned out to be the entity transmembrane voltage,
defined as V
m
= V
i
- V
o
. Ling electrodes make the measurement possible, as diagrammed below.

The following are three examples illustrating just how important the signal V
m
turns out to be.

First, there is the hot stove example and the reflex arc comprised of neurons.

Heart muscle

Figure 1. Schematic of classic method for
measuring transmembrane voltage, a lingua
franca of life at the molecular and cellular level.
Figure 2. Flow of information from pain of hot stove to reflexive retraction of limb (left). Heat is converted to
nerve action potentials (right) in afferent neuron. This results in nerve action potentials in interneuron located
in spinal cord. This in turn leads to action potential conducted down motor neuron. This results in activation
of muscle, resulting in retraction of limb out of harms way. Absence of this sort of unconscious reflex
protection results in limb decimation in diseases like diabetes.
Page 3

Second, each beat of the heart is initiated by a much longer, but analogous action potential in heart
cells. Without such action potentials, the heart would be quiescent, and death would ensue.

Third, regulation of a critical biological fuel, glucose in the blood, depends critically upon bursts of
action potentials in beta cells of the pancreas. Remember this as the late-afternoon chocolate bar
syndrome.

Despite the fact that action potentials spanning vastly different durations were involved in the three
phenomena described above, the three scenarios all involve the common language of electrical
signals. Moreover, there was a deep-seated hope that the same fundamental mechanisms gave rise
to all of these action potentials. Thus, there might be something akin to a unified field theory of
physics, if we could understand the biological basis of electrical signal generation.

Figure 3. Action potential recorded from
beating mammalian heart cell. Note duration
spanning 100s of msec, versus 1-3 msec
duration of action potentials in neurons.
Figure 4. Bursts of action potentials, lasting seconds, mediate negative-feedback control of blood glucose
concentration. Left, transmembrane voltage records of pancreatic beta cell bathed in different concentrations of
blood glucose. Elevated glucose causes depolarization, even leading to bursts of action potentials. These
bursts trigger secretion of a hormone called insulin, which signals other cells to lower blood glucose, a crucial
brain food that must be kept within normal limits. Right, feedback information flow controlling blood glucose
levels. Hypoglycemia (too low blood glucose) causes you to feel drowsy in part because the crucial brain food
of glucose is too low. That accounts for the refreshing rush of a chocolate bar late in the afternoon. The
disease of diabetes fundamentally involves a disturbance of the feedback loop at right.
Page 4

2. Ionic channelsthe magic behind electrical signals

At the heart of electrical signal generation are transmembrane-spanning proteins called ionic
channels. In man-made electrical circuits, transistors and other active components are crucial to
generating interesting electrical tricks; getting a Radio Shack kit with only passive parts like resistors
and capacitors is pretty boring. In regard to biological electrical signals, ionic channels turn out to
be the crucial active, nonlinear components, which undergird the vastly different action potentials in
section 1. Thus, ionic channels are the magic underlying electrical signals.

This being the case, we will devote considerable attention to these molecules. Following this, we
will see how they combine in cellular membranes to produce the action potentials used in electrical
signaling.

A. Protein ultrastructure of a prototypical ionic channel

Channels are essentially a very specialized hole in the membrane bilayer. Shown below is a low-
resolution cartoon of the ultrastructure for a nicotinic acetylcholine receptor channel.

Figure 5. Cartoon ultrastructure of a nicotinic acetylcholine receptor channel. When open, these ionic channels
conduct Na
+
ions through a central pore. Note the characteristic dimensions: the pore spans the 30-50 angstrom
thickness of the cell membrane. The channel is composed of five subunits, comprised of two alpha subunits,
and single beta, gamma, and delta subunits. The large outer portion of the channel at top (extending into the
extracellular media) is decorated with various sugar molecules (branch-like structures). The smaller
cytoplasmic portions of the channel at bottom are anchored by anchoring proteins (cigar-shaped structures).
Page 5

B. Primary sequence and presumed folding pattern of ionic channels

For most ionic channels, however, explicit determination of ultrastructure has not yet been
accomplished. However, it is believed that the overall idea of a fancy hole in the membrane will
hold true. In the meantime, we do know the primary sequence of amino acids that comprise just
about all ionic channels. From these we can infer the folding patttern (secondary structure) in the
membrane by hydropathy analysis (greasy spoon index), which can be benchmarked against
actual ultrastructure of solved ionic channel structures. The basic primary sequence and presumed
folding pattern of three major classes of voltage-gated channels (Na, K, and Ca channels), the
movers and shakers of action potential generation in the vast majority of cells, are as follows.

i. Na, K, Ca made of four homologous domains
ii. Big: about 2000 oo
iii. Each homologous domain with 6 putative membrane-spanning regions.

Figure 6. Inferred folding pattern (secondary structure) and ultrastructure (right) of voltage-gated ionic channels. Left, the folding pattern
starts with an intracellular amino terminus, and ends with an intracellular carboxy terminus. The folds occur according to four
homologous domains, as numbered by Roman numerals. Each domain seems to have 6 transmembrane spanning regions, as predicted
from hydropathy analysis. Right, inferred way in which homologous domains array themselves at the ultrastructural level to form ionic
channel in 3D. The domains are like the staves of a barrel, and the pore would be along the central axis. K channels differ in that each
polypeptide would comprise only one domain. Four domains would come together to comprise a K channel.
I II III IV
I
II
III
IV
Page 6

C. Two major performance characteristics of ionic channels

The first characteristic is permeation, defined as how ions get through channels when open. There
are two subcharacteristics:

Selectivity = how picky channels are about which kind of ion they let through. This gives rise to the
"names" of channels, such as Na, K, Ca, ... channels.

Conductivity = property specifying the amplitude of current that will flow through a channel, given a
specified transmembrane voltage gradient, and given a specified [X]
i
and [X]
o
, where
X is a permeant ion.

The second major characteristic is gating, defined as how a channel opens and closes. There are
several types of gates, organized according to the signal that controls gate opening or closing:
Voltage-sensitive (Na, K, Ca)
Chemical-sensitive (K
ATP
, nACHR, K
Ca
)
Stretch-sensitive
-sensitive

The selective and exquisite triggering of gates in different channels is crucial to custom action
potential generation.
Figure 7. Cartoon of voltage-gated ionic
channel, illustrating two major performance
characteristics of permeation and gating.
Permeation is a consequence of the narrow
selectivity filter. Gating is a function of the
intracellular gate, which is biased towards
opening or closing by electric fields acting on
the voltage sensor, the latter of which is
somehow coupled to the gate.
Page 7

3. Permeation in detail

A. Battery and resistor (BR) model

i. So long as a channel is absolutely selective for one species of ion, the voltage at which zero
current flows is absolutely specified by thermodynamics; it is not model dependent.
Thermodynamics yields the Nernst potential, the voltage difference across the membrane at which
no current will flow through the channel.

From previous lectures (last year) we have that the chemical potential energy is:
u
i
- u
o
is the change in energy of the system if one mole of ion X is moved from inside to outside the
membrane.

No current flows (equilibrium) when u
i
=u
o
. Hence

It is worth emphasizing how the Nernst potential accords with intuitive deduction of the
transmembrane voltage required to hold net current at zero for a perfectly selective channel, which
in the example below is Na
+
.

V
F
z
+ P
V
+ ])
X
([ RT +
u
=
u
V
F
z
+ P
V
+ ])
X
([ RT +
u
=
u
o X p o o o
i X p i o i
ln
ln

X species for potential Nernst =
] [X
] [X

F
z
RT
=
V
i
o
x
x
|
|
.
|
\
|
|
|
.
|
\
|
ln

Figure 8. Intuitive confirmation of Nernst potential equation, involving balance of diffusive and electrical
forces.
Page 8

ii. Away from zero current (away from equilibrium), thermodynamics doesn't tell us what the value
of current should be. It is model dependent. Thermodynamics could tell us the direction of current
flow, and it is not unreasonable for the current-voltage relationship to be linear over a small range.
This could be modeled as a battery (= Nernst potential) in series with a resistor. Selectivity is
reflected in that the reversal potential = Nernst potential; this follows from our assumption that the
channel is perfectly selective for a given ionic species. Conductive properties are embodied in the
value of the resistance.

The equation statement of the two diagrams in Fig. 9 is I = g
x
(V
m
-V
x
).

iii. The proof of such a model (away from equilibrium) comes in the form of empirical
verification in many channel types. This simplest of models turns out to be one of the most useful in
constructing models of the cell, and in understanding how action potentials come about.

Figure 9. Battery-resistor model emerges from linear approximation away from Nernst potential.
Page 9

iv. The three problems/limitations of the battery-resistor (BR) model.

The first problem is how to account for imperfect selectivity in BR model. The ad hoc modification
is to postulate 2 (or more) independent pathways for ions X and Y, each with its own Nernst
potential battery.

In this case, i
channel
= i
x
+ i
y
= g
x
(V
m
-V
x
) + g
y
(V
m
-V
y
).

Simplifying this yields, i
channel
= (g
x
+ g
y
) (V
m
[ V
x
(g
x
/ (g
x
+ g
y
)) + V
y
(g
y
/ (g
x
+ g
y
)) ])

This equation has nice intuitive appeal: the reversal potential (V
rev
, the entity in the [ ] symbols) is
the weighted sum of the Nernst potentials for ions X and Y, weighted by their relative conductances
g
x
and g
y
. This is a useful approximation under one set of ionic conditions.

The second problem comes with the intuitive certainty that conductance is going to vary with
different concentrations of permeant ions. In other words, from intuition based on the bathtub
analogy raised in class, it must be that g
x
= f(X
o
, Xi) and g
y
= f(Y
o
, Y
i
). The BR model has no theory
to account for the forms of these functions. As a concrete example of the reality of these functions,
consider the figure below. The bathtub analogy will make it obvious that conductance, in the
presence of only ion X in equal concentrations on the inside and outside, should increase with
concentration of X.

Figure 10. Ad hoc BR model modification to
account for imperfect selectivity of channel to
ions X and Y.
Figure 11.
Consequence
1 of bathtub
analogy
Page 10

The third problem is a second related consequence of the bathtub analogy, which arises when the
concentration of a permeant ion X is unequal on the inside and outside. This results in the
phenomenon called rectification. Again, the BR model has no theory or means to account for this
realistic property of channels.

B. Electrodiffusion model (solved with the constant field assumption) = Goldman-Hodgkin-Katz
Equation

One of the earliest attempts to address these problems was made by Hodgkin et al using the Nernst-
Planck electrodiffusion equation. We develop this in detail because so much of our "first-order
approximation" logic derives from this model.

In this model, the channel pore is viewed as an isotropic slab of material. The layout is as follows.

Figure 12. Consequence 2 of bathtub analogy logic: prediction of rectification.
Figure 13. Layout and
assumptions of GHK
current equation model.

> >
constant E-eld
(slope is constant)
Page 11

This layout can be solved for the GHK current equation as follows. Start with the Nernst-Planck
electrodiffusion equation, which describes current flow through this slab of material (current/area).

| |
a b

Part a in the Nernst-Planck electrodiffusion equation has to do with simple diffusion, tantamount to
Fick's law or random walks. This part is fairly straight forward.

Part b is more unusual. It has to do with the establishment of a certain drift velocity determined by
the balance of friction and electrical force applied to a permeant ion in the channel.

Solving this equation with the boundary conditions and constant-field assumption in Figure 13 (see
Appendix 1), yields the following solution.

Substituting the permeability coefficient for ion X, defined as the entity P
x
= (D
x
| / d), yields the
final equation. This equation is the famous Goldman-Hodgkin-Katz current equation, or GHK
current equation (units of current per cross-sectional area; D
x
has units of length
2
-sec
-1
). Multiplying
by the cross-sectional area of a single channel a gives the single-channel current.

x
x x x,i o
dX( ) F d
Z
= + + X( )
J Z FD
d RT d
_
_
_ _
| | | |
| |
\ . \ .

exp
1 exp
x m
i o 2
x x
x,i o m
x m
F
V -Z
-
X X
( F RT ) Z D
=
J V
F RT d
V -Z
-
RT
|
| | | |
| |
| |
\ .
|
|
| | | \ .
| |
\ . \ .

exp
1 exp
x m
i o 2
x
x x,i o m
x m
F
V -Z
-
X X
( F RT ) Z
=
J V P
F RT
V -Z
-
RT
| | | |
| |
\ .
|
| | |
| |
\ . \ .

Page 12

It is worth learning how to sketch the predicted behavior of the GHK current equation, as illustrated
in the diagram below. Note the use of extreme-voltage asymptotes to produce the sketch.

With the current equation in hand, we can proceed to engage another famous perspective of this
model, as emodied in the GHK voltage equation. The heart of this latter equation comes from the
realization that we can now predict I
T
, even when the channel is not perfectly selective. From the
property of independence, we can write

I
T
= I
1
+ I
2
+ ..... + I
n

where each of the I
i
terms on the right are GHK current equations for each of the different types of
permeant ions for an imperfectly selective channel.

To predict the reversal potential (V
rev
), set I
T
= 0, yielding

I
T
= 0 = I
Na
+ I
K
+ I
Cl

where Na, K, and Cl might be permeant ions for a generic channel in question. Plugging in explicit
GHK current equations for the Na, K, and Cl terms, and solving yields the GHK voltage equation
stated below.

(
Cl P
+
K P
+
Na P
Cl P
+
K P
+
Na P
F
RT
- =
V
i Cl o K o Na
o Cl i K i Na
rev
ln

Figure 14. Asymptote analysis of GHK current equation reveals ability to predict property of rectification.
Page 13

C. GHK-like models fit poorly with physical features of ion channel permeation

Problem with GHK model is that it is hard to make the conceptual link between permeabilities and
channel architecture. Moreover, channels are not isotropic slabs, they have discrete features. In
other words, the GHK model is not a very "physical" model. Here we present the Reuter-Stevens
model for two reasons. 1) To emphasize how one might begin to construct a physical model, and 2)
To emphasize that the description of current flow (outside of equilibrium conditions) is inherently
model dependent. There is nothing God-given about the GHK equations.

Some realistic features point to shortcomings in the GHK model. These arise from the first
crystal structure of a real ion channel, taken from a watershed paper from Rod
MacKinnons laboratory.

From previous mutagenesis studies of K channels, the part of the secondary structure that seemed
important for permeation was the P-loop shown as a dark black segment between S5 and S6
transmembrane segments in the figure below.

Figure 15. Permeation
segment of channel
secondary structure, as
suggested by mutagenesis
of K channels.
Page 14

In the crystal structure, shown below, we can appreciate the 3D nature of the permeation pathway,
lined in large part by portions of four P loops, each contributed by different subunits.

Three realistic features of ion channel permeation emerge from the crystal structure, and these are all
at odds with the isotropic-slab depiction of the GHK model.

(1) Single-filing of K ions through a narrow pore.

(2) Discrete residence sites (binding pockets) in the channel pore; possibility of saturation, at odds
with independence assumption of GHK model, and at odds with constant diffusion coefficient
through the thickness of the channel incorporated in the GHK model.

(3) Close quarters imply ion-ion electrostatic interaction within the pore; clearly not in agreement
with independence assumption of GHK model.

These features are more clearly depicted by the cartoon abstraction of the crystal structure below.

Figure 16. Crystal structure of Kcsa potassium channel, from bacteria. Upper surface is the outside of the
channel, inner surface is the cytoplasmic aspect of the channel. Left, ribbon diagram of two opposing
subunits, showing GYG segment of P loops in red. Right, stereo view of cutaway of channel, showing high
density positions of potassium ions (shown in green) in the channel pore.
Figure 17A Cartoon abstraction of permeation
mechanism, inferred from actual crystal
structure of Kcsa channel.
Page 15

These physical features (single filing) fit nicely with the functional property of an abrupt size cutoff
of permeant ions in Na channels. This would not be anticipated by the isotropic-slab view of the
GHK mechanism.

Figure 17B Na channel permeability as a
function of various permeant cations with
different diameters. Illustrates abrupt size
cutoff of permeability, consistent with
permeation through a discrete, narrow hole or
pore.
Page 16

D. Free-energy barrier (Reuter-Stevens) model, simplest quantitative mechanism with a taste of
physical reality

Constructing a fully realistic quantitative model of channel permeation, with complete fidelity to all
known physical features, is an enormous undertaking beyond the capabilities of the fastest
computers (see B Roux (2002) Theoretical and computational models of ion channels. Curr Opin
Struct Biol 12:182-189).
However, we can formulate a simple mechanism that gives a taste of physical models, called the
barrier, or Reuter-Stevens model. This model serves to introduce the approaches to constructing
more realistic models, and to introduce a very powerful approximation used to describe the discrete
ion or protein movement so prevalent in biology. The latter approximation is called the Eyring rate
theory, which we will develop later below.
We begin formulation of the barrier model, by considering what happens when permeant ions (K
+
in
the case of K channels) move single-file among discrete positions in the permeation pathway. On
theoretical grounds, we expect there to be some oxygensfrom amino acid side chains (glutamate,
aspartate, serine) or even backbone carbonyl groupsto take the place of water, the later of which
energetically stabilizes permeant ions in free solution. The free energy analog of this would be
different height free-energy barriers that different ionic species must traverse.

In the barrier model, we quantify the motion of ions across such an energy barrier using an
extremely powerful approximation called Eyring rate theory. According to this theory, the
probability that ion B (in Fig. 18) will jump over the barrier to become ion D, within a small
increment of time At, is simply given by the expression

k At P(B)

where k is a rate constant pertaining to this transition, and P(B) is the probability that an ion resides
at position B. Not only does the theory posit that a rate constant k exists, the theory also gives the
value of k in terms of the free-energy barrier profile (Fig. 18, right). It turns out that the exact
features of the barrier need not be known, only the activation energy AG
act
, the free energy required
Figure 18 Free-energy
depiction of permeant ion
jumping from one stable
position to another.
AG
act

outside
inside
Page 17

to boost a mole of ions from position B to position C. In terms of this parameter

k = ( k
B
T / h ) exp [-AG
act
/ (R T)]

where k
B
is Boltzmanns constant, T is the absolute temperature in Kelvin, h is Planks constant, R is
the gas constant, and ( k
B
T / h ) has units of reciprocal time (like sec
-1
).

Hence, and intuitive rationalization of the Eyring functional form is this: First, (k
B
T / h) gives the
number of barrier crossing attempts per second that one ion in position B would make to scale
the entry barrier. Second, the fraction of these attempts that result in successful ion leaps over
the barrier peak is given by the exponential factor exp(-AG
act
/RT).

For simplicity, the Reuter-Stevens barrier theory assumes that there are no binding sites within the
pore of the channel, only a single barrier that a permeant ion must jump to get clear through the
channel pore. In this sense, the Reuter-Stevens barrier model is unrealistic in that it becomes an
independence model, where doubling the concentration of permeant ion simply doubles the rate of
ion transport through a channel. We dont have to make this assumption, as Eyring-rate-theory-
based models can easily incorporate binding sites within the permeation pathway, but this is best left
to exercises outside of the lecture.

Even so, the Reuter-Stevens barrier theory is every bit as good as the complicated GHK model in
predicting channel behavior, except that the underlying assumptions are more physical in the
barrier theory. Heres how we get an explicit current equation from the barrier assumption. The
assumption of no binding sites means that the entire model need only consider two rate constants: k
oi

for B to D transtions, and k
io
for D to B transitions (see Fig. 18 for orientation). The explicit forms
for these rate constants, including the influence of electrical potential energy on the energy barrier
can be deduced as shown below, taking into account the addition of chemical and electrical potential
energy diagrammed below.

Based on this layout, we have:

This yields the RS current equation, given by [ ( ) ( )]
x
X io oi
= z F k P D - k P B
I
(current per mole
Figure 19 Summing chemical
and electrical potential free
energy to obtain the free-
energy profile of ion transit in
an ion channel pore. o is a
fractional electrical distance
ranging between 0 and 1.
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
RT
V
) - F(1
Z
+

RT
B
-

h
T k
=
RT
)) - (1
V
F
Z
-
B
( -

h
T k
= k
RT
V
F
Z
-

RT
B
-

h
T k
=
RT
)
V
F
Z
+
B
( -

h
T k
=
k
m x x B m x x B
io
m x x B m x x B
oi
o o
o o
exp exp exp
exp exp exp
Page 18

of ion channels), which yields the current flowing through a mole of channels, at steady state.
Channels reach their steady-state throughput in microseconds, so we only consider steady-state
responses for permeation equations.

Substituting the full expressions for the rate constants then yields

The remaining challenge, before this becomes a useful equation, is how to express P(D) and P(B) in
terms of bulk concentrations of ions X (X
i
and X
o
).

The simplest theory is P(B) = N
avogadro
C
V
X
o
, and P(D) = N
avogadro
C
V
X
i
. Here, C
V
is the
so-called capture volume, a volume (litre) near the mouth of the channel within which
permeant ions are considered to be within a molecular vibration of the entry barrier to the
channel pore. N
avogadro
C
V
is thus the expected number of permeant ions that would be within
the capture volume region, given an bulk permeant ion concentration X of 1 molar (= 1
mole/litre). X N
avogadro
C
V
thus gives the expected number of ions in the capture volume, and
for smallish X, where the expectation value is close to P(B) or P(D).

Now we can write the RS current equation in its fully useful form, with bulk concentrations
for X, as follows

Analog of permeability P
X

where this current flow through a mole of ion channels. It is worth sketching the predicted
behavior of the RS current equation, as illustrated in the diagram below. Note the use of extreme-
voltage asymptotes to produce the sketch.

|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
) ( exp ) ( exp exp B P -
RT
V
F z +
D P
RT
V
F z -

RT
B
-

h
T k
F
z
=
I
m X m X x B
x x
o
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|
|
.
|
\
|

o
m X
i
m X x B
V avogadro x x
X -
RT
V
F z +
X
RT
V
F z -

RT
B
-

h
T k
C N F
z
=
I
exp exp exp
o
Figure 20. Asymptote analysis of RS current equation reveals ability to predict property of rectification.
Page 19

Further things to check out with RS model.

1. The V
rev
for one ionic species predicted by the Reuter-Stevens current equation is the same as
for the GHK current equation. It has to be since this situation corresponds to thermodynamic
equilibrium. In fact, both equations simplify to the Nernst Potential equation at V
rev
. Away
from V
rev
, that is away from equilibrium, the Reuter-Stevens and GHK equation differ. This is
as it should be since thermodynamics no longer constrains behavior, and the current flow is then
model dependent.

2. Do both Reuter-Stevens and GHK current equation account for rectification and [X
i
] and [X
o
]
dependence of limiting conductances?

3. Does the Reuter-Stevens model handle imperfect selectivity? Say cations X and Y are both
permeable. Is there a Reuter-Stevens model prediction for current in this case?

Flaw with all mechanisms thus far in lecture is that they all leave out ion-ion interaction in the
pore, and that there is no ion binding within the pore. Both of these possibilities would lead to
non-independence behavior.

4. Summary

- Electrical signals are a major language of life at the molecular/cellular level.
- Ion channels are the magic behind electrical signaling, knowing their permeation and gating
properties will afford great insight into action potential genesis and signaling.
- Covered overall architecture of ion channels: how K versus Na/Ca channel differ, homologous
domains, transmembrane spanning regions
- Nernst potential: what it means, where it comes from (equilibrium thermodynamics)
- Battery-resistor permeation model: underlying assumptions, how to use it
- The classic model. GHK permeation model: underlying assumptions, intuitivebasics of NP
electrodiffusion equation, how to use GHK current equation, how to use GHK voltage
equation. Dont have know how to derive it.
- What is K
csa
?
- The simplest physical model is RS barrier model. Know how it comes from Eyring rate
theory, underlying assumptions, how to use RS current equation.
- At the core of the RS barrier modelEyring rate theory: know this fundamental theory

Next lecture we will put the channels back together and see how they determine membrane
potential. We will also begin to consider gating properties in detail.

Page 20

Appendix 1: In-depth derivation of GHK current equation

Part a of the Nernst-Planck electrodiffusion equation comes straight from diffusion theory and will
not need to be derived. Part b comes from the following considerations. Note, in this derivation, l =
d from Figure 13.

J
Page 21

J
J
J
J
J
Page 22

Appendix 2: Intuitive interrelation between GHK and BR models, classic Eric Young

J
J
J
J

Electrical Signals I - 2012

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Electrical Signals I - 2012

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