neurons can thus, neurons have

rest leak (&, in some cells, other) channels

transduce stimulus energy
into electrical signals
stimulus-gated channels
generate a spike
voltage-gated Na & K
channels
release neurotransmitter
onto other neurons & onto
other tissues (muscle, etc)
voltage-gated Ca channels
respond to input from other
neurons
transmitter-gated channels
transduce stimuli
process signals
produce involuntary
responses
generate & control
behavior
extract information &
intellectual activity
overall functions afferent & efferent signals
receptor ending, dendrite, axon, terminal,
polarity, rest, response, neurotransmitter
today & next week
4 cells
responding
1
2
3
4
summary
formation of extracellular
fluid in periphery & in CNS
1) measure the voltage across the
membrane.
2) plot the voltage as a function of
time.
3) present or remove the stimulus, or
change the stimulus intensity.
1
2
3
1) very negative resting potentials
e.g., ganglion cells in retina
2) less negative resting potentials
e.g., photoreceptors
3) oscillating rhythm
e.g., gastrointestinal system
4) pacemaker potential
e.g., cardiac SA node
-67 mV
-32 mV
B
a
y
l
o
r

8
4

J

P
h
y
s
i
o
l

B
a
y
l
o
r

7
9

J

P
h
y
s
i
o
l

H
o
r
o
w
i
t
z

9
9

A
n
n

R
e
v

P
h
y
s
i
o
l

examples of resting potential
K
a
u
p
p

0
1

A
n
n

R
e
v

P
h
y
s
i
o
l

for now, ignore the
response components
start with the easiest case
1) normal Na & K concentrations in extracellular fluid & cytoplasm,
abbreviate these as [Na]
o
& [Na]
i
and [K]
o
& [K]
i

2) cell membrane is permeable to K
+
ions
extracellular
mM
intracellular
mM
Na
+
150 15
K
+
5 150
Table
3-3
Na
+
ion concentration gradient
K
+
ion concentration gradient
K
+
leaves cell: efflux
K
+
enters cell: influx
K
+
tends to leave due to the K
+
concentration gradient.
As K
+
leaves:
1) negative charge inside cell exceeds positive charge.
2) positive charge outside exceeds negative charge.
3) This forms an electrical gradient (cell interior is negative, cell exterior is
positive).
4) This electrical gradient favors K
+
influx because...
a) The excess negative charge inside cells tends to pull K
+
back into cell.
b) The excess positive charge outside cells tends to repel further K
+
efflux.
K
+
efflux
K
+
influx
QUESTION: do K influx & efflux ever completely stop?
ANSWER: look at next few slides.
1) Unlike other channels, this path is
always open.
2) It allows K to leak into & out of
cells.
3) So this is called a leak channel.
measure E
m
& change [K]
o
5K
B
i
n
d
o
k
a
s

9
4

J

N
e
u
r
o
p
h
y
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l

K
u
f
f
l
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r

6
6

J

N
e
u
r
o
p
h
y
s
i
o
l

as [K]
o
increases
1) more + charge enters
2) E
m
becomes less negative
as [K]
o
decreases
1) more + charge leaves
2) E
m
becomes more negative
if K
+
moves, what happens when you change [K]
o
?
K
u
f
f
l
e
r

6
6

J

N
e
u
r
o
p
h
y
s
i
o
l

The line drawn through the data shows the values predicted by the Nernst
equation for K
+
ions at room temperature (23
o
C)
E
K
= 59 log ([K
o
]/[K
i
])
This states that
1) E
K
is determined only by the K concentration difference, at a fixed
temperature. There are no other variables in this equation.
2) the electrical force (voltage) acting on K
+
ions is balanced by the
chemical force (concentration difference) acting on them. Thus, this
describes K
+
ions when they are in electrochemical equilibrium.
Because the forces are balanced,
the rates of K influx & efflux are
equal.

Kuffler 66 J Neurophysiol Hodgkin 59 J Physiol
Notice the small discrepancy between E
K
& E
m
(at low [K]
o
values)

A revised equation fits the data better: E
K
= 58 log ([K
o
] + 0.01[Na]
o
)/140
i.e. membrane potential (voltage) is proportional to K
+
concentration difference and a
small fraction of the Na
+
concentration. This implies that the resting membrane is
slightly permeable to Na
+
ions.
QUESTION: how can you test this possibility?
if E
rest
depends on [K]
o
/[K]
i
and on [Na]
o
,
1) how are these concentration gradients formed?
2) how do K & Na move across resting membranes?
Na-K ATPase forms K
+
and Na
+
ion concentration gradients
7
th
ed: Fig 3-17
8
th
ed: Fig 3-16
bind Na
+
release Na
+

on extracellular side

bind K
+
release K
+
on intracellular side

phosphorylation
de-phosphorylation
http://www.bnl.gov/
bnlweb/pubaf/pr/2003/
bnlip100803.htm
ions dont diffuse through channels like they do through water.
they are bound to water (in an aqueous solution).
to move through a channel, they must shed at least some of this water,
bind to amino acids in the wall of the channel, and then unbind from
these amino acids.
X + water
X + O
X + water
1) sequence of many amino acids.
2) contains 4 hydrophobic segments (M1, M2, M3, M4)
that span the membrane lipid bilayer (pink).
3) these separate hydrophilic segments that
extend into the extracellular (above) or
intracellular (below) uids.
4) two of these sequences form one ion channel.
Thus, each protein is a subunit. The leak
channel is a homo-dimer -- a complex of two
(di) identical (homo) subunits.
P
a
t
e
l

0
1

T
r
e
n
d
s

i
n


N
e
u
r
o
s
c
i
e
n
c
e

2
4
:
3
3
9

M M M M
M3 M4
M2
M1
M1
M2
M4 M3
The channel forms a hole (i.e., a pore) in the membrane. This pore allows
ions to move (passively and quickly) from the extracellular uid to the
intracellular uid, and from the intracellular uid to the extracellular uid.
The pore is lined by the P domains (P1, P2) of each subunit.
Imagine these domains as the inner surfaces of a tube, maybe like this:
P2
P1 P1
P2
side view of one subunit
end view of 2 subunits forming
1 homo-dimeric leak channel
X + water
X + O
X + water
rotate
90
o
amino acid sequences shown in orange extend
carbonyl (C=O) groups toward the pore interior.
the oxygens might form rings around the pore. in
other K-channels, the diameters of these rings are
similar to that of unhydrated K ions, but they are
larger than unhydrated Na ions.
thus the spacing and charge of the oxygens creates a
selectivity lter, and allows the channel to be
K-selective (i.e., pass K and not Na ions).
T
h
i
s

i
s

n
o
t

a

l
e
a
k

c
h
a
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l
,

b
u
t

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e

a
m
i
n
o

a
c
i
d
s

t
h
a
t

b
i
n
d

t
h
e

K

i
o
n
s

a
r
e

t
h
e

s
a
m
e

i
n

l
e
a
k

c
h
a
n
n
e
l
s
.


M
o
r
a
i
s

e
t
a
l

0
1

N
a
t
u
r
e

4
1
4
:
3
7

K
+
ions (red balls in the left panel; blue balls in the right panel) unbind from the oxygens
of water (in cytoplasm or extracellular uid) and bind to the oxygens of the
carbonyl groups.
Depending on the electro-chemical gradients for K
+
ions, there will be a net
K
+
efux or inux.
T
h
i
s

i
s

n
o
t

a

l
e
a
k

c
h
a
n
n
e
l
,

b
u
t

t
h
e

a
m
i
n
o

a
c
i
d
s

t
h
a
t

b
i
n
d

t
h
e

K

i
o
n
s

a
r
e

t
h
e

s
a
m
e

i
n

l
e
a
k

c
h
a
n
n
e
l
s
.


M
o
r
a
i
s

e
t
a
l

0
1

N
a
t
u
r
e

4
1
4
:
3
7

where do the K ions bind?
look at the side view of a K channel, showing 4 ions inside the pore
summary
1) voltage is a net separation of charge. when this voltage exists across a
cell membrane, we call this voltage the membrane potential.
2) the membrane potential measured in the absence of stimuli is the
resting potential.
3) the resting potential of some cells is constant over time. the resting
potential of other cells might not be.
4) in a cell with:
a) Na
+
concentration gradient
b) K
+
concentration gradient
c) K
+
leak channels
the voltage is described by the Nernst equation for K ions. this equates
force due to concentration gradient & force due to electrical
gradient. gives us a voltage due to the combination of a permeability
and a concentration gradient, when the forces balance each other --
electrochemical equilibrium.
5) if the cell has K
+
leak channels & Na
+
leak channels, the resting
potential is some value between E
K
& E
Na
in this case, the resting
potential is not described by the Nernst equation for a single ion.
6) Resting potential forms in three steps:
a) Na-K ATPase forms Na & K concentration gradients.
b) leak K channels allow K efflux.
c) leak Na channels allow a small mount of Na influx.
If too much K
+
leaves the cell, the ATPase pumps it back in.
If too much Na
+
enters the cell, the ATPase pumps it back out.
Otherwise, the pump moves few ions & E
rest
is set by P
K
& P
Na
.
7
th
ed: Fig 3-23
8
th
ed: Fig 3-22