Review
Prepare: Nice 3D visualization of neurons: https://youtu.be/Zqtng0AfHFY
Hydrophilic (charged and
polar) molecules LOVE
water molecules.
They come very close.
Hydrophobic
molecules are
afraid of water.
They push
water
molecules away.
Charged molecules
Uncharged
extra electrons or lack of electrons
(=positive charges) that can interact
with water molecules
Polar
Nonpolar
electrons are
distributed unevenly
creating spikes of
charges that can
interact with water
molecules
Ions: K+, Na+, Cl-,
Ca++
H2O, Urea,
O2, CO2, N2,
glucose,
fats, oil,
proteins petrol/gasoline
Hydrophilic
Hydrophobic
Over 3.4 billion years ago… cells surrounded
themselves with a border
Can molecules and ions (O2, CO2, N2, K+,
Na+, Cl-, Ca++ , H2O, Urea, glucose, proteins)
penetrate through a cell membrane?
0.1nm
(nanometer)
10µm
0.006µm
= 6nm
Appreciate cell membrane
thickness: if you scale a cell
to the size of a house, then
membrane thickness will
be similar to the house
wall thickness
Charged: extra
electrons or lack of
electrons
Uncharged
Polar
Ions: K+, Na+, Cl-,
Ca++
Nonpolar
H2O, Urea,
O2, CO2, N2,
glucose,
fats, oil,
proteins petrol/gasoline
Hydrophilic
Membrane-impermeable
Hydrophobic
Membrane-permeable
• Biological membranes have all kinds of proteins inserted:
channels, pumps, transporters, receptors – up to 100 million
of transmembrane proteins
• Water channels (aquaporins) are found in most cells
Na+ – K+ pump (Na+ – K+ ATPase)
Ringer
solution
K+
+
+
K+
-
+
+
-
+
+
-
+
+
- +
+
+
++
+
- +
++ - - +
+
+
+ - +- + -+
- +
- + - +
+
- +
+
+ +
+- +
+
-
+
+
+
-
-
- +
+
+
+
++
+ - +
-+
+
-
+
[K ]=150mM
K+
K+
-
K+
K+
[K+]=4mM
• Potassium concentration is greater inside the cell  net flow
is from inside to outside
• How many potassium ion will leave the cell before the
equilibrium is reached?
• The correct answer is counter-intuitive
• The correct answer: 2 million out of 0.5 trillion potassium ions
will leave the cell = 0.0005%
+
-96mV
-
K+
+
+
K+
-
+
+
-
+
+
-
+
+
- +
+
+
++
+
- +
++ - - +
+
+
+ - +- + -+
- +
- + - +
+
- +
+
+ +
+- +
+
-
+
+
+
-
-
- +
+
+
+
++
+ - +
-+
+
-
+
[K ]=150mM
K+
K+
-
K+
K+
[K+]=4mM
• At equilibrium, voltage across the membrane = -96mV
• Potassium leakage channels are present in all cells
• Potassium leakage channels are always open, not
regulated by voltage across cell membrane
New Slides
1. All
potassium
channels are
open. All other
channels are
closed
-96mV
?
K+
+
+
K+
-
+
-
-
+
+
K+
+
+
+
+
-
+
+
-
+
+
- +
+
+
++
++
- +
+
+
- +
+
+ - -- + +- + -+
- +
- + - +
+
- +
+
- + +
+- +
+
+
-
+
++
-
+
-
+
+
- +
+
+
+
++
+ - +
+
-+
+
+
-
[K ]=150mM
[Na ]=15mM
+
+
+
K+
K+
K+
[K+]=4mM
[Na+]=145mM
• Na+ – K+ pump generated high [K+] concentration inside, low [Na+]
concentration inside.
• Potassium is leaking out through leakage channels (we say high potassium
permeability PK).
• How will charge distribution across cell membrane look at equilibrium?
(compare to the iPhone touchscreen capacitive display)
• What voltage will we measure across cell membrane at equilibrium?
+
-96mV
?
–
+
–
+
–
+
–
+
–
–
+
–
–
–
+
–
+
+
+
–
+
+
+
+
–
–
+
–
+
–
+
–
+
–
+
• Every time another potassium ion leaves the cell, it adds to the force that
pushes potassium ions back into the cell.
• Within milliseconds an equilibrium is reached
• It is reached after just 2 million out of 0.5 trillion potassium ions leave the cell
= 0.0005%
• If you now insert an electrode and measure electrical potential what number
will you measure?
• Potassium equilibrium potential is the voltage across cell membrane at which
the net flow of potassium across cell membrane is zero.
–
+
Ringer
solution
2. All
Potassium
channels are
closed. All
sodium
channels are
open (we say
high sodium
permeability
PNa).
-
Na+
-
+
-
-
+
+
-
-
+
+
+
+
-
-
-
-
+
-
+
-
+
+
-
+
-
+
+
-
-
+
- +
+
- +
+
++
+
++
- +
+
+
+
+
- +
++
+
+ - +
++ - +- + -+
+
-+
+
- + - +
+
- +
+
+
+ +
+- +
+
+
+
+
+
+
+
+
[K ]=150mM
[Na ]=15mM
Na+
-
+
+
-
+
+
+ -
+
+
-
+
-
-
[K+]=4mM
[Na+]=145mM
• Will sodium concentration equilibrate across cell
membrane?
+60mV
?
-
Na+
-
+
-
-
+
+
-
-
+
+
+
+
-
-
-
-
+
-
+
-
+
+
-
+
-
+
+
-
-
+
- +
+
- +
+
++
+
++
- +
+
+
+
+
- +
++
+
+ - +
++ - +- + -+
+
-+
+
- + - +
+
- +
+
+
+ +
+- +
+
+
+
+
+
+
+
+
[K ]=150mM
[Na ]=15mM
Na+
-
+
+
-
+
+
+ -
+
+
-
+
-
-
[K+]=4mM
[Na+]=145mM
• What voltage will we measure across cell
membrane now at equilibrium?
3. Equal
number of
potassium and
sodium
channels are
open (PNa= PK).
0mV
?
K+
+
+
-
Na+
+
+
-
-
+
+
-
+
+
- +
+
+
++
++
- +
+
+
- +
+
+ - -- + +- + -+
- +
- + - +
+
- +
+
- + +
+- +
+
-
+
-
-
- +
+
+
+
++
+ - +
-+
+
-
[K ]=150mM
[Na ]=15mM
K+
++
-
+
Na+
+
-
[K+]=4mM
[Na+]=145mM
• What voltage will we measure across cell
membrane at equilibrium? Why?
-88mV
?
K+
+
+
-
Na+
+
+
-
-
+
+
-
+
+
- +
+
+
++
++
- +
+
+
- +
+
+ - -- + +- + -+
- +
- + - +
+
- +
+
- + +
+- +
+
-
+
-
-
- +
+
+
+
++
+ - +
-+
+
-
[K ]=150mM
[Na ]=15mM
K+
++
-
+
Na+
+
-
[K+]=4mM
[Na+]=145mM
4. A more real scenario:
# of open potassium channels = 100
# of open sodium channels
1
• What voltage will we measure across cell membrane at
equilibrium? Why?
+58mV
?
K+
+
+
-
Na+
+
+
-
-
+
+
-
+
+
- +
+
+
++
++
- +
+
+
- +
+
+ - -- + +- + -+
- +
- + - +
+
- +
+
- + +
+- +
+
-
+
-
-
- +
+
+
+
++
+ - +
-+
+
-
[K ]=150mM
[Na ]=15mM
K+
++
-
+
Na+
+
-
[K+]=4mM
[Na+]=145mM
5. Another real scenario:
# of open potassium channels = 1
# of open sodium channels
100
• What voltage will we measure across cell membrane at
equilibrium? Why?
+60mV
PNa>> PK
+58mV
PNa / PK = 100 / 1
Depolarized
0mV
PNa= PK
-88mV
PNa / PK = 1 / 100
-96mV
PNa<< PK
Resting membrane potential
Hyperpolarized
• At rest some potassium always leaks out
• This outflux is counterbalanced by the Na+ – K+ pump
• Note: in the first approximation:
Na+ permeability (PNa) is proportional to # of opens Na+ channels;
K+ permeability (PK) is proportional to # of opens K+ channels
Respect membrane potential
• Electric ray – electric discharge can paralyze or disorient a prey
• Discharge originates from electrocytes (modified muscle cells
• Peak voltage = 50 Volts
•
•
•
•
The eels’ electricity-producing organ has both a positive and negative end, with the positive
end at the head and the negative end in the tail. By curling their bodies, the eels is bringing
the opposing ends of its organ closer together to concentrate the stunning effect.
they can "remote control" their prey, forcing them to twitch (and thus reveal their location).
Once the eels shock their quarry, they reposition it in the water so they can swallow it headfirst.
To find out if this was what the eel’s prey was feeling, researchers took brain-dead fish
equipped with electrodes, put it near an eel as bait, and measured the voltage applied when
the eel attacked. Sure enough, the fish received more than double the voltage when the eel
curled its body, bringing the opposite ends of its electricity-generating organ together.
The eel then would batter the prey’s body with a series of shocks that forced the
unfortunate animal’s muscles to contract until they reached exhaustion, effectively
paralyzing the animal temporarily and making it safe for the eel to release and reposition it.
+60mV
PNa>> PK
+58mV
PNa / PK = 100 / 1
Depolarized
0mV
PNa= PK
-88mV
PNa / PK = 1 / 100
-96mV
PNa<< PK
Resting membrane potential
Hyperpolarized
• Most important: cells can regulate membrane potential by
changing PNa / PK ratio over time
• Increase to 100/1 for 1ms. What happens?
• Voltage jumps to +58mV
• Reduce to 1/100 -- What happens?
• Voltage drops to -88mV
+60mV
PNa>> PK
+58mV
PNa / PK = 100 / 1
Depolarized
0mV
PNa= PK
-88mV
PNa / PK = 1 / 100
-96mV
PNa<< PK
Resting membrane potential
Hyperpolarized
• We have just found a way to transmit
information
• All neurons communicate with these transient
(1ms long) spikes called action potentials
How to transmit information over long distance?
We will consider two hypothetical solutions:
1. make one long cell:
At rest:
-80mV
-80mV
-80mV
-80mV
-80mV
Change membrane potential at cell body:
+30mV
+10
-20
-40
-80mV
-80mV
-80mV
• Signal dies without reveling to the cell terminal
• In a real cell, signal dies over 2 mm (1/1000 of the
distance to the muscle of the toe)
• Why?
+30mV
+10
K+
-20
-40
K+
-80mV
K+
-80mV
-80mV
300°C
200°C
• Analogy: heat transmission along a metal rod
immersed in water
• Did you transmit any heat to the far end of the rod?
120°C
60°C
30°C
Heat escapes
from the
metal rod
Metal rod
25°C
20°C
20°C
Water temperature=20°C
+30mV
+10
K+
-20
-40
K+
-80mV
K+
-80mV
-80mV
• Ions escape from a
long neuron
Possible solution #2: Connect many cells sequentially
-80mV
-80mV
-80mV
-80mV
-80mV
-80mV
+30mV
-80mV
-80mV
-80mV
-80mV
-80mV
-80mV
+30mV
-80mV
-80mV
-80mV
-80mV
-80mV
-80mV
+30mV
-80mV
-80mV
-80mV
-80mV
+30mV
….
-80mV
-80mV
-80mV
-80mV
• Each cell amplifies the spike to +30mV, then activates to following cell.
Possible solution #2: Connect many cells sequentially
• The downside of this system:
• There is a delay at every electrical junction
between the cells.
• The distance from motor cortex in the brain to
the toe muscle = 2meters.
• 2meters / 20micrometers cells = 100,000 cells
• Assume that inside a cell electrical signal is
transmitted instantaneously
• Delay between cells = 1millisecond
• Total transmission time = 100,000 x 1ms =
100s = almost 2 minutes
• Too long!
• This mechanism is only used
– over very short distances in animals
– over long distances in plants
Solution: make one long cell and amplify along the way
At rest:
-80mV
-80mV
-80mV
-80mV
-80mV
Change membrane potential at cell body:
+30mV
-80mV
-80mV
-80mV
-80mV
Amplify along the way:
-80mV
+30mV
-80mV
-80mV
-80mV
-80mV
-80mV
+30mV
-80mV
-80mV
-80mV
-80mV
-80mV
+30mV
-80mV
-80mV
-80mV
-80mV
-80mV
+30mV
• Make one long cell and amplify along the way
• This principle is used throughout the nervous system
amplified
amplified
• An action potential
visualization: An action
potential traveling along
an axon can be visualized
as a flame racing along a
fuse or a sparkler, each
segment igniting the next
until the action potential
reaches the end of the
axon.
Dendrites
amplified
Cell body
Initial segment
amplified
Axon
collateral
Axon
Axon
terminals
Golgi stain
Camillo Golgi (1843 – 1926) accidentally elbowed over a beaker of silver solution onto some
brain slices. To his surprise, silver stained the slice in peculiar manner. Under the microscope, he
saw neuronal cell bodies, dendrites and axons … But Golgi thought that all neurons of the brain
are electrically connected together and act as a reticulum.
Here comes Spanish
neuroanatomist Santiago
Ramón y Cajal (1852–1934)
Cajal was the first to see
discrete neurons 
Neuronal doctrine: neurons
are electrically isolated
Ramon y Cajal improved Golgi' staining by
using a method he termed "double
impregnation." Ramon y Cajal's staining
technique, still in use, is called Cajal's
Stain.
“Like the entomologist hunting for brightly
colored butterflies, my attention was
drawn to the flower garden of the gray
matter that contained cells with delicate
and elegant forms, the mysterious
butterflies of the soul, the beating of
whose wings may some day (who knows?)
clarify the secret of mental life. […] Even
from the aesthetic point of view, the
nervous tissue contains the most charming
attractions. In our parks is there any tree
more elegant and luxurious than the
Purkinje cell from the cerebellum or the
psychic cell, that is the famous cerebral
pyramid?"
Santiago Ramón y Cajal, 1894
Purkinje cell located in the cerebellum
• Still Cajal found his neuronal doctrine hard to sell.
• He had to launch his own journal to propagate his
ideas.
• Eventually Cajal’s drawings got attention and, in a
twist of irony, Cajal and Golgi (two scientific
rivals) shared a Nobel prize in 1906.
• Nice 3D visualization of neurons: https://youtu.be/Zqtng0AfHFY
Dendritic spines
Dendritic spines
Branch of Neuroscience: Cellular neuroscience
A smarter way to amplify signal along the axon
Amplifications stations (sodium channels)
amplified
amplified
•
•
Instead of amplifying continuously
Amplify only here.
•
Electrically isolate everywhere else.
•
•
•
•
Isolation does not let charges (ions) escape from the cell 
It allows a cell to amplify signal less frequently 
Faster signal transmission
Most neurons in mammalian CNS are myelinated
Oligodendrocyte
300°C
• One myelin-forming cell (called
oligodendrocyte) can wrap around a
number of axons (up to 40)
• The number of myelin layers is 10 to
160 (what is the number of
membranes?)
• Analogy: metal rod immersed in water,
but this time we put multiple layers of
thermal isolation over the rod
300°C
Cross
section of a
nerve:
which axons
are
myelinated?
Cross section of optic nerve
This neuron expresses an
fluorescent die-tagged protein
that turns up exclusively on the
axonal cell surface.
Example of axonal
transport
axon
The bright spot in the cell body
corresponds to the Golgi area where
the carriers originate.
Functional differences of axons and
dendrites hinge upon differences in their
molecular composition. Membrane
proteins destined to either of the
domains leave the Golgi in
tubulovesicular carriers that are
transported by molecular motors along
microtubular tracks.
Molecular motors dynein and kinesin carrying their
cargo along microtubular tracks
• Biological membrane is a dynamic structure
• Diffusion of phospholipids and some
transmembrane proteins is possible inside the 2dimentional surface of a membrane
Example of fusion
of membrane
protein with cell
membrane
Delivery of membrane proteins to the cell surface occurs by fusion
of the carriers with the plasma membrane. Two fusion events
have been captured fortuitously in this movie. Upon fusion, the
contents of the carriers very rapidly diffuse in the plasma
membrane, resulting in a fleeting impression of a railroad track
due to the optical sectioning power of the microscope.
Time lapse: 30 seconds (one loop of movie)
• The internodal distance is ~100 x external diameter of the axon
• Usually from 200 micrometers to 2 mm
Conduction velocity
Time to cover 2 meters
Myelinated
5 to 120 m/s
(10-270 miles/hour)
2meters / 100m/s = 20ms
Unmyelinated
<2m/s
(<4 miles/hour)
2meters / 2m/s = 1s
•
•
•
•
•
•
Myelin sheath does not let ions escape,
so that current flows only at nodes of Ranvier
 Excitation jumps from node to node:
saltatory conduction (from the Latin saltare, to hop or leap)
Fewer ions enter and leave the cell 
less metabolic energy is required to restore intracellular
concentration of potassium and sodium
+60mv
+58mv
PNa>> PK
PNa / PK = 100 / 1
+30mv
Depolarized
0mv
-88mv
-96mv
PNa= PK
Resting membrane potential
Hyperpolarized
PNa / PK = 1 / 100
PNa<< PK
• DEFINITION: Action potential is the jump of membrane
potential (Em) from resting Em of -80mV to +30mV for
1ms during the amplification process.
• How do we measure action potential?
Amplification process
• Main player: voltage
activated Na+ channel
• At rest: PNa/PK = 1/100
and Em is close to EK
(Em=-88mV)
• Na+ channel is closed at
Em=Em resting
• As Em is increasing to
-40mV, Na+ channels
start to open.
• We say -40mV is a
threshold for Na+
channels.
+60mV
?
-
Na+
-
+
-
-
+
+
-
-
+
+
+
+
-
-
-
+
-
+
-
+
+
-
+
-
+
+
-
-
+
- +
+
- +
+
++
+
++
- +
+
+
+
+
- +
++
+ - + - +
++ +- + -+
-+
- +
+
- + - +
+
- +
+
+
+ +
+- +
+
+
+
+
+
+
+
+
[K ]=150mM
[Na ]=15mM
Na+
-
+
+
-
+
+
+ -
+
+
-
+
-
-
[K+]=4mM
[Na+]=145mM
Recall: Voltage-gated channels
outside
inside
Resting membrane potential:
inside is negative
Cell is depolarized: inside is positive
Voltage-gated Na+ channel
– – –
+ + +
-88mV
-40mV
+ + +
+
– – –
+
+
+
+
– – –
+ + +
+
Na+ channel closed
•
•
•
•
– – –
+
+ + +
+
Na+ channel open
What ions are coming into the cell through an open Na+ channel?
Positive sodium ions.
How are they changing membrane potential?
They make the membrane potential even more positive.
+30mV
?
– –
– – –
+
–
-
-40mV
-
+
+
-
+ +
+ + +
+
•
•
•
•
•
Na+
+
+
+
-
+
-
-
+
+
-
-
+
+
+
+
-
-
-
+
-
+
-
+
+
-
+
-
+
+
-
-
+
- +
+
- +
+
++
+
++
- +
+
+
+
+
- +
++
+
+ - +
++ - +- + -+
+
-+
+
- + - +
+
- +
+
+
+ +
+- +
+
+
+
+
+
+
+
+
[K ]=150mM
[Na ]=15mM
Na+
-
+
+
-
-
+
+
+ -
+
+
-
+
-
-
[K+]=4mM
[Na+]=145mM
membrane potential more positive
Even more sodium channels open 
Even more sodium ions enter the cells 
membrane potential even more positive  on so on ==
Positive feedback loop == explosion == gun powder
Node of Ranvier
– –
-40mV
– – –
+
–
+
+
+ +
+ + +
+
+
+
+
-40mV
-88mV
• So as Em reaches -40mV, practically all sodium
channels open  positive Na+ ions flood into
the cell  Em quickly jumps to +30mV
• Why doesn’t Em stay at +30mV?
– – –
+
+ + +
– – –
– – –
+
+ + +
• Why doesn’t Em stay at +30mV?
• Sodium channel inactivation!
• After 1ms the ball (protein)
blocks the channel 
• Sodium ions inflow stops 
• PNa / PK = 1 / 100 
• Em goes back to Em resting
+
+ + +
-88mV
– – –
+
+ + +
• The 2nd mechanism (less
important) that pulls Em
back to Em resting involves
delayed rectifying
potassium channel
-96mV
?
K+
+
+
K+
-
+
-
-
+
+
K+
+
+
+
+
-
+
+
-
+
+
- +
+
+
++
++
- +
+
+
- +
+
+ - -- + +- + -+
- +
- + - +
+
- +
+
- + +
+- +
+
+
-
+
++
-
+
-
+
+
- +
+
+
+
++
+ - +
+
-+
+
+
-
[K ]=150mM
[Na ]=15mM
+
+
+
K+
Afterhypopolarization
K+
K+
[K+]=4mM
[Na+]=145mM
• Find two errors:
Closed
Open
Inactivated
• Information transmitted by neurons is coded in
frequency of action potentials (firing frequency)
• Refractory period analogy = toiler flush
• An action potential spike
is initiated at axon
hillock
• There are more than
250,000 sodium
channels in axon hillock
– gun powder, explosion
• Axon transmits signal
actively (amplifies action
potential along the way)
• Dendrites transmit
signal passively (no
amplification) – there
are exceptions
Multiple sclerosis
• Symptoms: weakness
• Lack of coordination
• Impairment of vision and
speech
Lesions: the MS plaques in brain
and spinal cord white matter
• Outside the brain and spinal
cord, myelin is produces by
Schwann cells, that have
different origin and are not
attacked by the immune system
in MS
Diagnosis of MS: visual evoked potential
EEG
EEG amplitude
Normal
100ms
MS
delayed
Time
Light flash
• Profound slowing
of conduction
velocity and block
in some fibers
• Stop here
• The ONLY way for neurons to communicate
over long distance is by sending action
potentials.
• Over short distance, everything is used: action
potentials, chemicals and small changes in
electrical potential.
– – –
+
– – –
+ + +
+
+
+ + +
+ + +
+ + +
– – –
+
– – –
Inactivation
gate
Closed
Na+
Open
Inactivated