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Physiology Exam I Study Guide

Membrane Potentials
 Three things necessary to generate a membrane potential:
1. Ionic concentration gradient
- Active transport: ATP hydrolysis generates the energy to move ions against their concentration
gradients – mediated by trans-membrane pumps that hydrolyze ATP to generate the energy to
drive changes in transporter conformation and effect ion translocation
- Ex. Na+/K+ ATPase uses energy from ATP hydrolysis to transport 3 Na+ ions out of the
cell and 2 K+ ions into the cell, maintaining high intracellular K+ concentration and high
extracellular Na+ concentration
- Ex. Ca2+ ATPases extrude Ca2+ from the cell, keeping intracellular Ca2+ low
- The accumulation of many active transport pumps across the membrane creates the ion
concentration gradient
- The pumps do not contribute much to membrane potential directly
- Facilitative transport (pumps) work slowly, in the background rely on cellular energy ATP
2. Semi-permeable membrane
- Passive transport: ions and very small molecules massively diffuse across plasma membranes if
the membrane has ion-permeable channels; does not require the direct expenditure of metabolic
energy
- Ex. K+ ions flow passively out of the cell through K+-selective ion channels
- An electrochemical gradient for a given ion will produce net diffusion of that ion
- Selective ion channels within the membrane move many ions across the membrane and are
essential for generating an ion gradient and propagating membrane potentials
- These are aqueous pore through the membranes
- The channels have selective permeability
- It is just running down the gradient is what generates membrane potentials
3. Membrane capacitance (the ability to separate and store charge)
- The cell membrane surrounding the cell separates the inside from the outside and acts as a
capacitor
- The movement of charge changes the membrane potential and changes the voltage difference
- The passive efflux of K+ out of the cell generates a net negative potential inside the cell
- Resting cells have negative membrane potentials, because the plasma membrane holds excess
negative charges intracellularly and excess positive charges extracellularly
 Multitude of ion channel types:
o Ion channels come in many types, selective for particular ions
o Ex. Na+-selective channels that generate propagated electrical signals in nerve and muscle
o Ex. Ca2+ selective channels responsible for triggering release of synaptic transmitters and contraction of
muscle
o Some channels are always open, allowing persistent ion flux in the resting state, but for most, the opening
is gated/regulated by a stimulus to which the channel is sensitive
o The membrane potential is a function of the concentration of ions outside and inside the cell and the
relative membrane permeabilities to these ions

Generation of membrane potentials:

 Equilibrium potential: the electrical force equal in magnitude, but opposite in direction, to the chemical force (ie.
the concentration gradient) for a specific ion
1. Imagine a cell with high intracellular
concentrations of K+ and an anion A-
2. If you open K+ selective channels in the plasma
membrane, K+ becomes permeable to the
membrane and it flows passively out of the cell,
down its concentration gradient

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3. Since the anion A- is impermeable to the membrane, negative charge builds up inside the cell, creating an
electrical potential across the membrane
4. The electrical potential counteracts the force of the K+ concentration gradient, forcing K+ to flow back
into the cell through its ion channels
5. When the electrical force pulling K+ into the cell is equal in magnitude (but opposite in direction) to the
chemical force generated by K+ concentration gradient, K+ will be in equilibrium
6. At K+ equilibrium potential (EK), potassium will not move across the membrane in either direction
 Nernst equation: mathematical depiction of an ion’s equilibrium potential; if a cell is permeable to only one ion
type, then the cell’s membrane potential will be equivalent to that ion’s equilibrium potential
Eion = equilibrium potential of the ion
R = gas constant – 8.32 J/molK
T = absolute temperature
RT [ion]outside F = Faraday’s constant (96,500 coulombs/mol)
Eion = × ln z = valence of the ion (ie. its charge, K+ has a
zF [ion]inside valence of +1, Ca2+ has a valence of +2)
[ion]outside = extracellular concentration of the ion
[ion]inside = intracellular concentration of the ion
- At normal body temperature: RT/zF x ln is
about 60 mV/z x log (if the permeable ion
under consideration is a monovalent cation that is 10x more concentrated inside than outside the cell, then
Eion would be -60 mV
- If that ion is the only permeable ion, then the actual membrane potential would also be -60mV
inside relative to outside
- Denominator > numerator  negative number
- Numerator > denominator  positive number
- Looking at sodium: sodium is positively charged, and concentrated on the outside much more so than the
inside; so it will flow in, not out; as sodium flows in, positive charge follows, resulting in the inside being
positive, creating the force driving them  ENa would be
+60mV
- Looking at chloride: chloride is concentrated outside and
it is negative; so the gradient forcing the chloride will
drive it in, but as that happens, the inside becomes
negative, so the electrical force is outside; but still get -
60mV because the “z” term is (-) not (+)
- Looking at calcium: it has a low concentration outside,
but very low inside; the log is big because the free calcium
concentration inside is so low; the equilibrium potential
turns out to be even more positive
- Cl-, Na+, K+ generate almost all of the important current
flows
- Resting membrane potential (Em) is influenced only by
permeable ions
- K+ is the most permeable ion. If K+ were the only permeable ion, it would be the only ion
contributing to the resting membrane potential, and Em would be equal to EK. In reality, Em is
slightly less negative than EK, indicating that other ions contribute to the resting membrane
potential. In addition to K+, other ions like Na+ contribute a small amount to the resting potential
of the cell, so Em lies in between EK and ENa
- The influence of any ion on Em is proportional to that ion’s relative permeability
- When multiple ions are permable, the more permeable a given ion, the closer the actual membrane
potential will be to the ion’s equilibrium potential
- The number of ions it takes to move the membrane potential will not change the ion concentration that
much

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 The amount of charge that it takes to move/change the membrane from -60 to +60 is tiny
compared to even the inside concentration or low outside concentration of the three major ions
 BUT: because calcium have such low concentrations inside, the calcium that comes in is
significant enough to change the concentration
- In the short term, total ionic concentration gradients do not change significantly with changes in Em

Selective permeability of Cell membranes

 Largely permeable to potassium – this is the predominant open
channel in resting membrane
 If you raise the potassium channel:
o Outside: 48, the log changes and the resting membrane
potential increase
o Inside: 4  1, this will increase driving force and the
resting potential will become negative
 By changing the extracellular concentrations of potassium, you can
greatly alter the electrical properties
 Cell membranes are very K+-permeable and also slightly Na+-
permeable
o There is a linear relationship between the changing concentration in Potassium and then the membrane
potential
The actual membrane potential:
 It is between Ek and ENa
 The actual membrane potential is a composite of the Nernst potentials of
the various ions that can flow
o It is principally potassium and sodium
 Cell membranes are very K+-permeable and also slightly Na+-permeable
o There is a linear relationship between the changing concentration
in Potassium and then the membrane potential
 The difference between actual and then the equilibrium for potassium is
small
o Most of the channels are open for potassium
 The driving force for sodium is huge, but the membrane potential stays
down because the number of sodium channels open is a tiny fraction of the
number of potassium channels open at rest
 The cell can change Em by varying sodium vs. potassium open channels
o If the number of sodium channels open increases, it will pull the membrane potential up to ENa

The membrane is a simple circuit

 There are ion channels embedded through which ions flow
 Lipids give rise to capacitance, changing ions moving inside to
outside
 For a passive membrane, the change in Em is a function of
strength of injected current
 The relationship between the change in Em and injected current for
a passive membrane is linear
o The change in membrane related to injected current
 The passive resistance determines the magnitude of Em to injected current; small
cells have higher resistance than large ones
o If the resting passive potassium channels are there at a certain
concentration, then a cell with a small area, will have fewer channels, so
injecting current will produce a bigger change in the membrane potential
o Ex. In a muscle fiber compared to a nerve, the size difference is huge and
you have to have a huge synaptic current to move the potential a significant

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amount
 Signals get smaller as they spread down axons, dendrites and muscle fibers
o Need a mechanism for amplifying the signal or else the signal will not be
able to travel the whole length
o Signals will eventually peter out, so there needs to be a way to amplify
o The signals get smaller because current “leaks out” along the way
o The leakier the membrane, the less far the signal will spread
 Plot the voltage as a function of length, it will decay exponentially
o The length constant – lambda
 It is the length at which the signal falls to 1/e (~1/3) – it depends
on variables
 The bigger axon will have a longer length constant
 If you have a high membrane resistance, or have insulation, it will have a longer length
constant
o Myelin is a type of insulation that keeps the current from leaking out
o Make axons bigger or insulate

Action potentials generation and conduction This is an all-or-none response

 The changes in ion flux alter the membrane potential and the There is a threshold of the action potential so
change in potential, if large, will trigger a response that if you make a stimulus that is too small,
 Channel there will not be an action potential triggered
mediated
changes in The action potential does not just reach zero,
membrane it crosses, goes positive and that is because of
potential: the sodium channels opening up
o When a The peak is due to an increase in voltage-
cell gated sodium channel permeability
receives Rapid fall, is due to sodium conductance
stimulus decreasing and the potassium increasing
that
triggers opening of ion channels, the change in plasma membrane permeability initiates current flow
across the membrane, which alters the membrane potential
o The stimulus will make the cell more negative inside, or less negative, depending on which ions can pass
the channels and the electrochemical gradient of the ions
 The channels that make long-distance conduction possible are gated by changes in membrane potential
o The membrane capacitance is the lipid membrane
o And then there are resting channels that are always open, allowing for potassium ions to flow through
o To get an action potential: need channels that are not open all of the time, but gated in some way
o When the voltage-gated channels are open, they generate an action potential if there is enough
depolarization
o Voltage-gated channels are responsible for action potential
 Basic properties of action potentials:
o Voltage-gated channels are closed at normal resting potential, but open as Em becomes more positive
o Action potential produced only when the receptor potential is large enough to drive the membrane to
threshold
o Once threshold reached, the membrane produces a regenerative potential chane on its own, becoming
independent of the original receptor potential
o Action potential is all-or-none
o The membrane potential during the upstroke actually overshoots 0
o During falling, the AP moves to rest, but undershoots, becoming more negative than it is at rest
o Finally will return to normal
 To generate action potential, membranes need two kinds of voltage-gated channels
o Need channels selectively permeable to Na+ and K+
 Permeability can be linked to conductance
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When the channels are open, the current can flow, driving
the membrane potential in the positive direction, so when
there is no net flow, the inside will be at Ena, but when
the potassium channels open, the membrane potential will
be driven down toward Ek

Conductance measures the flow of ions going through

Ionic basis of the action potential

 The upstroke and overshoot depend on Na+ concentration
o If extracellular Na+ is reduced, the action potential rises
more slowly and the overshoot is smaller
o If you reduce the [Na+] outside, it makes ENa more
negative, lowering the peak of the AP
o The overshoot depends linearly on ENa
o The rise and peak of the AP are caused by a selective
increase in PNa
 The repolarization phase and undershoot depend on Ek
o During falling, the K+ is the predominantly permeable ion
o Increasing [K+] outside makes EK more positive and
makes the undershoot more positive
o The undershoot depends linearly on EK
o The falling phase and undershoot of the AP are caused by a
selective increase in permeability of K+
 So ENa and EK determine the overshoot and undershoot of the
action potential
 Temporal relationship:
o There is a fast selective increase in Na+ permeability, and
when the membrane depolarizes to threshold, Na+ channels
open, promoting Na+ influx and further membrane
depolarization
o When AP nears peak, the membrane stops being Na+ permeable and become K+ permeable
o Na permeability begins early and then inactivates, whereas K permeability begins more slowly and does
not inactivate
o

Right away the sodium rises, reaches peak

before the AP peak, and the K+ channels are
more sluggish
By the time get to peak of AP, the PNa is very
high before K+ channels open
Even though membrane potential is positive,
Na+ channels close quickly, and then the
potassium channels stay open, and it takes
longer for the potassium permeability to
come back down, which pulls the membrane
potential close to Ek

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There is a fast rise in the sodium permeability, then there are the
sodium channels closing
So by the end of the long pulse, when the membrane potential
steps down to resting, there is no change in sodium permeability
because all of the channels are in inactivated state; Closed state of
sodium, then the open state pushing the equilibrium toward open
state (high Na permeability) but then inactive, even though
membrane potential high
Only way to get into state where can be open again is to
repolarize the membrane and wait for the inactivation to change
from inactive to close
And only after that transition can they be opened again

Na+ channel conformations:

 Closed, but available to open in response to membrane depolarization
 Open
 Closed and unresponsive to membrane depolarization – this is the inactivated state
 The probability of Na+ channel opening varies as a function of
membrane potential
o The larger the stimulus, the larger the change in membrane
potential and the more Na+ channels open in response
o When a sufficient number of Na+ channels open to
overcome the resting K+ permeability (which holds Em at
resting), threshold is reached, and the depolarizing
upstroke of the AP begins
o Upstroke is explosive, Na+ influx depolarizes the cell,
opening more Na+ channels, producing more Na+ influex
and causing more depolarization
o Positive feedback = Hodgkin Cycle and is responsible for
the all-or-none nature of the AP
o If Na+ remained open, the Em would stay near ENa preventing any further AP  so two things allow
membrane potential to come back down:
 Na+ channel inactivation
 Large increase in membrane permeability to K+
K+ channels mediate AP repolarization
 As membrane becomes more depolarized, more K+ channels will open
 These do not inactivate
 Because they do not inactivate, the average current rises to a maximum and is maintained throughout the
depolarizing stimulus, generating outward flow of + charge
 Because of inactivation of Na+, there is a switch to K+ permeability, driving Em back to resting
 Because K+ permeability during the repolarizing phase of AP is higher than at rest, there is an undershoot, and as
Em becomes more negative, K+ channels close, letting
Em return to resting
The flow of ions during the production of a single AP does not
result in significant change in the concentration gradients for
Na+ or K+
Refractory periods
 Set limits on what frequency of action potentials are
possible
 With intervals of 10-20 ms, nothing changes
 As the time interval between two Aps decreases, the
threshold increases and the amplitude decreases
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 The threshold: is the level of depolarization needed to get the AP
 At shorter time intervals, the amplitude decreases and threshold increases
 The changes become larger as the interval between successive Aps gets shorter, until it is finally impossible to
trigger an AP no matter how big the stimulus is
 At intermediate intervals, the amplitude is reduced and the threshold is increased but it can still be possible to get
an AP
 The absolute refractory period: no AP at all, it is because the sodium channels are inactivated, so at very short
times, although the Na+ channels are closed, they CANNOT be open – there is a period of time you have to wait
before the sodium channels can open again
 The relative refractory period: a period when you can get AP of reduced amplitude, taking more depolarization;
this is caused by the fact that there is still potassium permeability
o The potassium channels have not fully closed yet, so have to depolarize farther to get enough sodium
channels to open so it is regenerative again
Action Potential shape is determined by the different voltage and time-dependent gating properties of Na+ and K+
channels
How are action potentials conducted without decrement?
 Passive conduction will not work
 But active conduction (using the AP) will work
 You have to use an AP and have to use a mechanism to reinforce the regenerative process because you have a
propagated signal
 Passive conduction in a leaky cable:
o The signal will get smaller and smaller
o The signal in a passive membrane, where no voltage
dependent channels exist, will eventually get smaller and
smaller
o If you inject a current, it will leak as it spreads down
How APs are conducted down axons (unmyelinated)
 There is an axon with a negative resting potential
 The sodium current is inward and will rise, while the potassium
will move out
 Some of the Na+ will enter and initiate an action potential; some of
the Na+ current entering at the stimulation site flows down the
inside of the axon or muscle fiber and depolarizes the membrane
some distance away from the original stimulus site
 If the depolarization is sufficient to open Na+ channels in the newly depolarized region, an AP will be produced
there
 The regenerative wave of depolarization will continue to move down the fiber as the Na+ influx through each new
group of Na+ channels makes a membrane depolarization opening neighboring Na+ channels
 Back at the stimulation site, the originally active Na+ channels are inactivating, while voltage-gated K+ channels
are activating to bring amount membrane repolarization
 The wave of repolarization also continues down the fiber, following the depolarizing wave at a brief delay,
completing the action potential cycle

Conduction velocity is a function of the length

constant
Large diameter axons conduct APs more rapidly
The threshold level: in an axon with a longer
length constant, the signal will travel farther
down, so will be able to initiate farther down than
one with a short time constant

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Action potential conduction in myelinated axons
 Occurs similarly to unmyelinated, but the membrane current flow is excluded from those portions of the
membrane covered by the myelin sheath
 Myelin is a multi-laminar insulation produced by Schwann cells and oligodendrocytes, which wrap themselves
around the axon
 Small portions of the axon membrane are exposed to the external solution
 Action potentials are generated only in the naked membrane regions – Nodes of Ranvier- because:
o Na+ channels are only localized in the nodes
o The myelin sheath forms an insulation that limits current flow through the intra-nodal membrane
 AP appears to jump from node to node
 Since Aps do not need to be regenerated by the membrane inside the myelin sheath, myelinated fibers conduct
APs more rapidly than do unmyelinated
 The myelin sheath makes the length constant longer even for the same sized axon
 Myelin sheath is adding insulation around the conductive part so that the current cannot leak out – current is
confined to the axon
 Do not want it insulated all along because you have to preserve the regions where the action potential can occur,
but want to insulate the regions so that the sodium does not leak out, but is still available in the unmyelinated part
 Internode region: insulated by myelin – this region is much longer than the node, which makes the conduction
speed faster in myelinated vs. unmyelinated axons with similar diameters
 Node: axon membrane is exposed
 To ways to make faster conduction: make the axon bigger OR more efficient by myelination

 Demyelinating diseases (ex. Multiple sclerosis): diseases causes by the degeneration of the myelin sheath
surrounding neurons, leaving large uncovered areas of axon void of Na+ channels
- Demyelinated axons are unable to propagate action potentials
- Na channels are still localized to the old nodes but the absence of myeling exposes the K+ channels to the
outside so the current can leak out along the way such that when it reaches the next node there may not be
any current left to initiate an AP
 If there is current left then a normal sized AP can be generated again
 The shape of an action potential is optimized; small changes in the shape can have drastic consequences
- Hyperkalemic Periodic Paralysis (HPP): disease caused by a mutation in Na+ voltage-gated channels
that causes them to get locked in an activated state, thus preventing membrane repolarization
- Autosomal dominant disorder
- Serum K+ levels may be slightly elevated so that Ek becomes more positive causing slight
depolarization
 If exercise, the K+ levels can go up cause
a depolarization that could trigger the Na
channels to open and then become inactive
and can get locked in this state
- The mutated channels cause the membrane to
become permanently depolarized, trapping wild-
type Na+ channels in an inactivated state
- When the majority of Na+ channels are inactivated,
action potentials cannot be produced and muscle
contraction cannot occur, leading to paralysis in
the limbs and trunk muscles
 This often occurs when there is a sharp increase in the K concentration
- Paralysis is transient, as the slow regeneration of resting membrane potential occurs due to flow
of K+ out of the cell
- Patients with HPP have acute, transient attacks of paralysis that increase in frequency after
exercise; in between attacks, they are asymptomatic
- HPP is inherited as an autosomal dominant trait (ie. only one mutant allele is necessary for
symptoms)

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 Cardiac action potentials have a different waveform and are
longer in duration than neuronal action potentials
- Cardiac action potentials are affected by Na+, K+, and
Ca2+
- Calcium influx is required for heart muscle
contraction and for the maintenance of
contraction for a longer period of time
(necessary to push all of the blood out of the
ventricles)
- Calcium flowing into the cell, causing depolarization,
and potassium flowing out of the cell, causing
repolarization, fight against each other and create the
characteristic plateau seen in cardiac Aps
- Because the Eca is very high and the concentration of Ca inside the cell is very low is is able to exert this
kind of effect
- AP triggered events
 Skeletal muscle – outside AP comes
down the T tubules and leads to the
release of Ca into the cytoplasm causing
a voltage change triggering the muscle to
contract
 Nerve terminal- AP can cause release of
neurotransmitters
 Synaptic vesicles at the end of
axon so that when the AP comes
in the voltage dependent Ca
channels opne causing the
vesicles to fuse with the
membrane of the axon and
release the contents of the
vesicles into the synaptic cleft
 Important conclusions
o V-gated Na+ channels produce regenerative inward current, V-gated K+ channels produce repolarizing
outward current
o AP shape is determine by diff voltage and time dependent gating properties of Na+ and K+ channels
o Loss of myelin sheath (MS) exposes a leaking intermodal memb which shunts regenerative current and
blocking conduction
o AP trigger a number of important physiological events (muscle contractions and synaptic transmission)
o Mts of Na+ channels cause a variety of diseases and pathological conditions

Axonal Transport
 Axons serve two major functions:
1. They propagate action potentials from the cell body to the presynaptic terminals
2. They provide a physical conduit for the transport of material between the cell body and the synapses
 Neurons are one of the most highly polarized cells in the human body
o They receive signals from other neurons through post synaptic sites along their elaborate and often
branched dendrites and send out signals through presynaptic terminals at the end of the their axons
 Axonal transport is important delivering membrane components and axon
guidance receptors during axon outgrowth
- During development, the growing axon uses transmembrane axon
guidance receptors on its growth cone to navigate the extracellular
environment

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- The tip of the axon sends out filapoda to fi nd the correct synaptic connections, then cell adhesion
molecules stabilize the synaptic junction
 Axonal transport is also responsible for trafficking cargo to and from the cell body
- Cargo includes membrane proteins, secretory vesicles, organelles, presynaptic machinery, cytoskeletal
components, axonal injury signals, and damaged proteins targeted for degradation
 Cargo destined for secretion originates in
the ER and traffics through the Golgi en
route to its final destination, such as the
plasma membrane
- Vesicle trafficking: cargo is
loaded into vesicles that bud from
the ER with the help of coat
proteins
- COPII coat proteins are
involved in vesicle
trafficking from the ER to
the Golgi
- COPI coat proteins are involved in retrograde transport from the Golgi back to the ER
- Clathrin coat proteins are responsible for post-Golgi vesicle transport (ie. to endosomes, the
plasma membrane, or back to the Golgi from these structures)
- Clathrin forms a triskelia structures and surround vesicles in a polyhedral lattice
- Clathrin adapter complexes confer binding specificity with the vesicle cargo
- A GTPase, dynamin, pinches off Clathrin-coated vesicles from the membrane
- Uncoating of the vesicle is required for fusing, an ATP-dependent process
- Vesicle Docking and Fusion: requires specialized machinery, called SNARE proteins
- v-SNARES: attached to the vesicle
- ex. Synaptobrevin
- t-SNARES: attached to the target membrane
- ex. SNAP-25 and syntaxin
- Tight binding between v-SNARES and t-SNARES
bring the vesicular and target membranes very close
together
- Fusion is regulated by small GTPases called Rabs
- Once the vesicle has fused with the target
membrane, the SNARE complexes are
disassembled by two proteins called NSF and -
SNAP
- The SNARES are retrieved by clathrin-mediated
endocytosis and can be reused
- Synaptic Vesicle Cycle

 Cargo moves along microtubules in the axon to get from the cell body to synapses (transport in membrane bound
organelles-MBOs)
- Axonal microtubules are oriented with their minus end near the cell body and their plus end distal to the
cell body (in dendrites, microtubules can run in either direction)
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- + end grows faster than the - end
- MTs provide the tracks on which MBOs are transported
- Motors (with the use of ATP) provide the power to moved the MBOs along the MT tracks
- Cargo can be moved toward the synapse (anterograde) or toward the cell body (retrograde)
- Fast anterograde transport (away from cell body)= most things, channels, orgnaells,
SVs)
- Slow anterograde transport= cytoskeletal elements
(NFs, tubulin, actin, clathrin)
- ATP-dependent motors provide the power to move cargo along the
microtubule tracks
- Kinesin: motor protein that moves toward the plus end of the
microtubule (anterograde transport in axons)
- Kinesin contains two motor heads that move step-by-
step along the microtubule (binding of ATP to a motor
head drives the other motor head forward; ATP
hydrolysis releases the motor head from the
microtubule, preparing it for its next step forward)
- Many types of kinesin exist, each with unique
tail domains that interact with different cargo
via adaptor proteins
 Motor domain, ATP binding motif, dimerization domain, PH domain
 KIFC= only kinesin that can move to the – end of the MT, all others move
towards the + end of the MT
- Dynein: motor protein that moves toward
the minus end of the microtubule (retrograde
transport in axons)
- Dynein movement is also ATP-
dependent
- Dynein is a complex of a large number
of proteins, suggesting that different
cargo interacts via different proteins in
the complex
- Dynein can bring signaling endosomes
carrying neurotrophic factors from
target tissues back to neuronal cell
bodies – important to neuronal differentiation and survival
- Involved in injury signaling- after axon injury dynein is needed to transmit s ignals from
the site of the injury to the cell body
- Transports lysosome and vesicles targets to the lysosome back to the cell body – required
for proper degradation of misfolded or damaged proteins in the axon
- Transports neurotrophic factors (BDNF and NGF)- dots on image on the right, and
signaling endosomes from target issues
back to the cell bodies – important for
neuronal diff and survival

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 Attachment of cargo to motors

o One motor can transport many diff types of cargo
o Each motor uses its unique tail domain to either interact directly or indirectly with cargo through
associated proteins called adaptors
o Association of cargo with adaptors or with the motor can be regulated by posttranslational modifications
like phosphorylation
o Motors have redundant functions and one type of cargo is often transported by multiple motor family
members
 Traffic signals for motors
o MTs are modified by many post translational signals that act as traffic signals telling the motor what to do
 Diseases of Axonal Transport
- Mutations in any of the motors or associated proteins important for axonal transport can lead to
neurologic disorders
- A common feature of several neurodegenerative diseases is the abnormal accumulation of proteins and
cargo in axons
- Amyotrophic Lateral Sclerosis (ALS): dominant mutation (G59S) in the microtubule binding domain of
the dynactin subunit of dynein results in protein misfolding leading to protein aggregation in axons
- Huntington’s Disease: Huntington associated protein (HAP1) binds to dynein and kinesin;
overexpression of the huntingtin gene results in axonal transport defects
- Hereditary Spastic Paraplegia: mutation in kinesin; disease characterized by progressive spastic motor
neuron degeneration of lower extremities
- Charcot Marie Tooth Disease: progressive neurodegenerative disease characterized by peripheral
neurodegeneration due to a mutation in kinesin

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