03_Action Potential_Q and A_Jonathan Flashcards Preview

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1

What is capacitive current?

• Across a capacitor: upon injection of current, initially the increase in positive charges in the cell will cause the accumulation of negative charge on the inside of the membrane to be reduced/dispersed, which leads to the accumulation of positive charges on the outside of the membrane to decline as well.
• the redistribution of charges across the membrane is equivalent to current flow across the membrane, although no carriers of charge (ions) actually cross the membrane

2

What is ionic current? ((???))

• As the discharging of the capacitor nears completion, more and more of the injected current contributes to the current flow across the membrane in the form of ions, as the steady state ion fluxes re-equilibrate - this is called the IONIC CURRENT.

So the initial charging of the membrane capacitance causes a lag in the onset of the ionic current flow, which in turn is responsible for the lag in the change in membrane potential.

3

What is the time constant?


• The time constant is the time required to rise to approximately 63 % of the total change in potential.
• For most neurons, the time constant is between 1 –10 milliseconds.

4

Why is the time constant important?

• The rate at which the membrane changes in response to an individual stimulus and its subsequent relaxation determines how closely spaced sequential stimuli must be before there is summation of their effects.
• Longer time constant = greater summation of stimuli and possibility of reaching threshold upon repeated stimulation

5

What are cable properties?

• Most neurons have long processes or axons. They have many of the same electrical properties as an undersea cable. For this reason, the electrical characteristics involved in the spread of current and voltage changes along an axon are called CABLE PROPERTIES.

6

In the equivalent circuit, the axon is divided up into short segments or rings, and for each, there is the membrane resistance and capacitance for that segment, as well as a resistance to current flow through the inside of the axon, which is represented as ri.

In the equivalent circuit, the axon is divided up into short segments or rings, and for each, there is the membrane resistance and capacitance for that segment, as well as a resistance to current flow through the inside of the axon, which is represented as ri.

7

What is the length constant?

• The LENGTH CONSTANT (λ) is the distance (in centimeters) at which ~37% of the original change in membrane potential still occurs. A shorthand formula that is worth knowing is:
______
λ = √ (rm / ri) where
λ = the length constant (in centimeters)
rm = membrane resistance
ri = internal resistance to current flow

In most cells, the length constant is usually between 0.1 and 1.0 millimeters.
( about the distance in the nodes of ranvier)

8

What is the speed of propagation?

* membrane resistance (rm), membrane capacitance, (Cm) and the internal resistance to current flow (ri) affect the SPEED OF PROPAGATION is proportional to

1/ sqrt (Rm x Ri x Cm)

Consider:
rm ∝ 1/Diameter
ri ∝ 1/(Diameter)2
C ∝ Diameter

This means that AS THE AXON DIAMETER INCREASES (and the membrane resistance (rm) decreases, the capacitance (C ) increases, and the internal resistance to current flow (ri) decreases a great deal), THE SPEED OF PROPAGATION INCREASES. Thus, the squid giant axon has a high speed of propagation (which is a good thing for the squid....).

9

What is an action potential?

• a rapid depolarization and then repolarization of the membrane in response to a membrane depolarization of sufficient magnitude (not hyperpolarization).

10

Compare Na and K channels in response to depolarization.

• Na channels
o open in response to depolarization
o inactivates rapidly (despite maintained depolarization)
o needs repolarization before it can be active again
o depolarizes
• K channels
o Delayed opening in response to depolarization
o Does not inactivate
o Closes upon repolarization
o Repolarizes
o Note: there are many subtypes of K channels
• Delayed rectifying channels
• others

11

What is the threshold potential?

• The THRESHOLD is the membrane potential at which the inward current through the Na channels that are opening up is finally greater than the outward K current through other channels ( INa > IK+ ILeak.)
• Na channel activation and inward current and thus a very rapid positive feedback cycle is begun.
• The depolarization also activates K channels, but they have a more sluggish response to depolarization and there is a lag before this conductance becomes appreciable, so it does not prevent this cycle from occurring.

12

Note: Na/Katpase does not play a role in action potential

The PROPORTION OF IONS THAT MOVE DURING AN ACTION POTENTIAL IS SMALL, and their intracellular concentrations will vary by less than one thousandth of the total.

Note: Na/Katpase does not play a role in action potential

The PROPORTION OF IONS THAT MOVE DURING AN ACTION POTENTIAL IS SMALL, and their intracellular concentrations will vary by less than one thousandth of the total.

13

Explain ion selectivity in an ion channel?
What aspects of an ion channels allow for selectivity?

• Size on Hydrated Ion: Na channel is not large enough for an K, but is large enough for an Li
o Hydrated radius of Na-H2O vs K-H2O
• Energy of hydration: K channel is large enough for dehydrated K, but not for hydrated Na.
o Since K is easier to dehydrate than Na, the channel pore loop pulls H2O off of K and allows K to pass through. The pore loop is not strong enough to dehydrate Na, so Na-H2O is too large to pass through.
• Note: the pore loops are what select for ions.
o Ex: if we change the amino acid structure of the pore loop, we can change an Na channel into a Ca channel

14

Explain the Voltage sensitivity of the channel

• S4 region senses voltage. Other aspects of the channel remain unchanged
o Has an unusual alpha helix
• Inside of the helix usu has only non-polar
• S4 has some charged amino acids which allows it to respond to voltage
• Arginine or lysine every third amino acid
o Differences in S4 regions between Na and K cause differences in speed of opening (Na fast, K slow)
o Areas of investigation: Paddle model vs helical twist model

15

Note: patch clamping allows f to measure the current of a single ion channel.

Note: patch clamping allows f to measure the current of a single ion channel.

16

Explain inactivation of ion channels. What are the differences between K and Na channels? What are the components?

• K channel inactivation
o Ball and chain on N terminus
• Has 4 ball and chains (only 1 ball needs to plug the channel)
o Ball is + charged
o When cytosol becomes thoroughly depolarized, the ball plugs the channel
• Na channel inactivation
o Small flap of + charged aminos
o When the cytosol becomes depolarized, the flap blocks the channel
• Note: there are 80 types of Na and K channels, not all inactivate

17

Explain the basic difference between T-type and L-type Ca channels?
Where are each located?
What is the length of opening?

• T-type
o Located at presynaptic terminals of nerve cells
o Open to release neurotransmitters
o Think “transient”
• L-type
o Found in cell membranes of the cell body
o Long-lasting

18

Explain the rate of opening of Ca channels compared to Na and K channels?

• Opening faster to slower: Na > Ca > K
• Closing faster to slower: Na > K > Ca

19

Remember the Ca plateau: Ca channels take longer to close than Na or K channels. How does norepi affect Ca plateau? What is the mechanism?

• shortens the duration of the action potential ie, the Ca plateau is shorter
• Norepi binds to G protein ==> βγ subunits binds to Ca channel and inhibits the channel ==> less Ca flows in and stays open shorter time
• Ex: this can be negative feedback. If norepi is released from neuron, it can inhibit the Ca channel of the same neuron
• Note: this occurs on Dorsal Root Ganglion nerves

20

What are delayed rectifier K channels?
Why are they slower to open than other K channels?
Why do they not inactivate?

• These K channels have one less + charged amino in their S4 region
• These K do not have a ball and chain to inactivate them
• Closed at resting membrane potentials and activated in response to membrane depolarization
• Their activation is usually slower than that for Na channels, and occurs with a slight lag

21

What is the IA current? What channel produces the IA current?

• The IA prolongs the depolarization of membrane, therefore increasing the length between repeated action potentials
• This is a K channel that causes the K current aka A current aka IA current
o These channels depolarize quickly compared to delayed rectifier K channels
• K flows out of these channels which attempts to hyperpolarize the cell. However, there are not enough to overcome the depolarization of the Na channels, so their only effect is to prolong the time of depolarization

22

What is the HCN channel? (Ih channel)

• Hyperpolarized and Cyclic Nucleotide-Gated channel
• They become activated at hyperpolarized states
• Influx of + ions, bringing the nerve from hyperpolarized back towards another threshold for a repeated action potential
• These channels are essential in pacemaker of rhythmically active cells
o Active area of study

23

How is the activity of HCN channels modulated?

• The activity of these channels is also modulated by cyclic nucleotides like cAMP
• HCN channels have a structure that resembles other voltage-gated channels
o 6 transmembrane regions in each subunit, pore loops, 4 subunits/channel
• Have an S4 region thought to undergo its shift in position in response to hyperpolarization.

24

What are Tetrodotoxin and Saxitoxin?

• bind to Na channels and block them
o high affinity and selectivity (no other channels are blocked)
• can cause death
• Details:
o TTX is from puffer fish
o STX is from “red tide” algae and may infect fish, at which point it is fatal

25

What are Conus Toxins?

• a class of toxins that block Ca channel

26

What is tetraethylammonium (TEA)?

• a K channel-selective blocker, the outward K current is no longer observed in response to depolarization, but the inward Na current is unaffected.

27

Compare TTX to TEA?

• TTX, the inward Na current is blocked, while the outward K current is unaffected.
• TEA, the outward K current is no longer observed in response to depolarization, but the inward Na current is unaffected.

28

How do Procaine and Lidocaine work?

• Binds to the S6 region of the 4th domain (detail)
• Use-dependent block. Only blocks, once channel opens. As channels open, more channels get blocked going forward
o Perfect for pain because many nerves attempt to fire and become blocked.
o Therefore the lidocaine preferentially blocks pain nerves and not so much other nerves

29

Explain the hyperexcitability of severed nerves? How does this related to phantom limbs?

• The end of a severed nerve ending of may grow into a tangle of axons and swollen nerve endings known as a neuroma.
• There is often an accumulation of voltage-gated Na channels in these bulbous nerve endings, and the hyperexcitability in this region may result in a chronic sensation sensation of pain, or phantom pain.
o VSSC = Voltage-Sensitive Sodium Channel

30

What are channelopathies?

• Disorders characterized by mutations in voltage-gated ion channels that result in abnormal ion channel activity and neuronal excitability

31

What are some characteristics of the mutations in channelopathies?

• voltage-gated channels that do not activate or inactivate properly
• Examples
o Na channels may open quickly, but do not inactivate properly
o Or may “re-open” several times during a single depolarization.
• Mutations associated with seizures and epilepsy include
o voltage-gated Na channels
o voltage-gated K channels
o voltage-gated Ca channels
o or hyperpolarization and cyclic –nucleotide gated (HCN) channels

32

Note: action potential propagation requires both passive and active spread of depolarization

Note: action potential propagation requires both passive and active spread of depolarization

33

Unidirectional action potential propagation when started in the axon hillock. If the axon is stimulated mid axon, the AP will travel in both directions.

Unidirectional action potential propagation when started in the axon hillock. If the axon is stimulated mid axon, the AP will travel in both directions.

34

What is the Axonal Initial Segment (AIS)?

• aka the axon hillock: site for the initiation of action potentials in neurons.
• an accumulation of cytoskeletal and membrane proteins, including voltage-gated Na channels and K channels
• It also serves as a “barrier” that restricts diffusion and spread of proteins between the axonal compartment and the somato-dendritic compartment of a neuron.

35

Smaller diameter axons → slower
Change in size and function depending on the purpose of the neuron

Smaller diameter axons → slower
Change in size and function depending on the purpose of the neuron

36

What is the effect of myelin on capacitance and speed of neuron and the length constant?

• myelin ↓↓↓↓ capacitance and ↑ rm
• SPEED OF PROPAGATION ∝ 1/ √ (rm x ri) x C
• LENGTH CONSTANT( l ) = √ (rm / ri)
• Therefore, ↑ speed of propagation and ↑ the length constant
• Essentially, myelination dramatically increases speed, therefore can decrease the diameter of the axon

37

What forms myelin in the CNS vs PNS?

• CNS: oligodendrocyte many nerves
• PNS: Schwann cell
o both unmyelinated and myelinated axons are surrounded by Schwann cells.
o In "unmyelinated" axons a single Schwann cell will "encase" or wrap around more than one axon
o one third of the peripheral nerves there is a more elaborate Schwann cell sheath that encases the individual axons

38

Note: ↑↑↑ Na channels at Nodes of Ranvier. Almost no Na channels under myelin

Note: ↑↑↑ Na channels at Nodes of Ranvier. Almost no Na channels under myelin

39

Describe the difference in development (fetal growth) of myelin in the CNS vs PNS

• IN THE CNS, the developmental expression and regulation of the myelin genes parallels the differentiation of the oligodendrocytes and exhibits little plasticity – it appears to be UNAFFECTED BY AXON presence or absence.
• IN THE PNS, Schwann cell expression of the myelin genes is entirely controlled by axons, and induction of these genes appears to DEPEND UPON AXONAL CONTACT.

40

How is the thickness of Myelin determined?

• In general, there are more wraps around larger diameter axons, and the ratio between the axon diameter and the myelin thickness is relatively constant.
o Called the “g ratio”
• The SIGNAL CONTROLLING MYELIN THICKNESS COMES FROM THE AXON.
o Ex: if transplant Schwann cells are transplanted to a region of unmyelinated axons, they myelinate according to axonal properties.
o Detail: Interestingly, the myelin finishes wrapping around the axon before the axon has finished growing to its final diameter, but the myelin sheath ends up appropriate for the final size of the axon.

41

What is Neuregulin?

• NEUREGULINS are transmembrane factors expressed in axons that determine myelin sheath thickness
• the receptor for them (the ErbB receptor tyrosine kinase.) is expressed on glial cells.

42

How does NRG expression effect size of myelin sheath?

• if express less neuregulin type III (NRG ), then see thinner myelin sheath
• if overexpress NRG, then see myelin sheath that is thicker than normal

43

Chicken or Egg… Nodes of Ranvier Na chanels cause even space of glial cells? Or vice versa?

• both. Ongoing cycle

44

What is myelin associated glycoprotein (MAG)?

• both CNS and PNS
• expressed in earliest stages of myelination, primarily in the first wrap
• involved in the initial axonal-glial recognition, adhesion, and initiation of myelination
• has an Ig-like structure (extracellular and transmembrane domains)

45

What is Po?

• PNS
• Accounts for 50% of myelin protein in PNS
• Mediates compaction
• Has + charge on surface to attract the – charge of the phospholipid myelin during wrapping

46

What is Proteolipid protein (PLP)?

• CNS
• The CNS equivalent of Po
• Accounts for 50% of myelin protein in CNS
• Mediates compaction
• Has + charge on surface to attract the – charge of the phospholipid myelin during wrapping

47

What is Myelin Basic Protein (MBP)?

• CNS and PNS
• proteins on cytosolic side, rather than extracellular side
• may mediate close apposition of innermembrane surface as cytoplasm is squeezed out

48

Why saltatory conduction?

• SALTATORY CONDUCTION IS ALSO FAVORABLE FROM A METABOLIC STANDPOINT, AS LESS ENERGY MUST BE EXPENDED BY THE Na/K ATPase IN ORDER TO MAINTAIN THE Na AND K CONCENTRATION GRADIENTS.

49

What is the difference between dysmyelinating diseases and demyelinating diseases?

• In dysmyelinating disorders, some form of myelin is present, but due to a genetic mutation or other biochemical defect, the myelin is abnormal in amount or composition.
• In demyelinating diseases, patches of the myelin sheath are absent.
• Note: in both axons are present and in good health

50

What is Guillain-Barre Syndrome? What is the etiology? Is it fatal? What is Tx?

• loss of myelin in the PNS affecting motor neurons
• Immune response and inflammatory damage to myelin
• Rarely fatal
• Give high doses of exogenous Igs and removing patients Igs

51

What is Multiple Sclerosis? What are symptoms? What cranial nerve is often implicated? What vitamin deficiency aggravates symptoms?

• Loss of myelin in the CNS
• Blurry vision, numbness, tingling, weakness, paralysis, incontinence
• Notable pathology of optic nerve
• Cyclic worsening of symptoms
• Vitamin D deficiency aggravates

52

What are suspected causes of MS?

• The cause of the disease is still unknown, but both environmental and genetic factors appear to be important.
• There is some evidence for factors (viral infection, stress, etc.) causing increased permeability of the blood -brain barrier to T lymphocytes.
• More prevalent in northern climates

53

What are myelin plaques?

• sheaths of myelinated fibers are lost and there is a substantial accumulation of activated astrocytes, microglial cells, and macrophages, leading to local gliosis.

54

What are treatments for MS?

• no effective treatment
• immunosuppressive (thought to be auto-immune disease)
o interferons and corticosteroids

55

What is Charcot-Marie-Tooth (CMT) Disease? What are the symptoms? What is the cause?


• Demyelination of PNS motor and sensory neurons
• Leg and hand weakness and sensory loss
• Caused by mutations in GAP junctions that connect the multiple layers of cytoplasm in the myelin sheath
o Gene: Cx32
• Note: this is a common illness

56

What about transplantation of oligodendrocytes for demyelination illnesses?

• promising results in animal models.
• For reasons that are unknown, however, the myelin in the “replacement sheaths” is typically thinner than the original myelin sheath.

57

What happens to the action potential propagation when the action potential reaches
a stretch of of de-myelinated axon? What happens to capacitance, resistance, length constant?

• ↑ membrane capacitance (cm)
• ↓ membrane resistance (rm).
o Has to flow a longer time in order to charge the membrane capacitance before it results in any ionic current flow and drives the adjacent membrane to threshold for an action potential
• the rate at which the depolarization spreads gets slower.
• ↓ Length Constant
o the local current will not spread as far as normal because it is flowing into a segment which (because of its low rm) has a shorter length constant.
o May not reach action potential

58

How does the body compensate for demyelination illnesses?

• Some “compensation” for the loss of myelin
o increase in expression of voltage-gated Na channels in the demyelinated segment
• Attempts to induce remyelination have so far only resulted in limited myelin formation, with the “new” myelin being thinner (having fewer layers) than the original myelin