Chapter 3 - Voltage-Dependent Membrane Permeability

Question 1

Prior to the 1940s, researchers found it challenging to study how the permeability of the membrane changes based on the membrane potential. Why in particular was this a challenge?

Answer 1

They had no way to simultaneously both control membrane potential and measure the permeability changes. An induced change in membrane potential will trigger an action potential, which causes “uncontrolled” changes in the membrane potential.

Question 2

In the 1940s, breakthroughs in neuroscientific knowledge of neuronal membrane permeability was made possible due to a new technique called ..

Answer 2

the voltage clamp method.

Question 3

What made the voltage clamp method so groundbreaking in the 1940s?

Answer 3

It allows researchers to control the membrane potential despite permeability changes that under normal circumstances would change the membrane potential further than the desired potential.

Question 4

The voltage clamp method permits the simulatenous measurement of the current needed to keep the cell at a given voltage. What is interesting about this data?

Answer 4

The current needed to keep the cell at a given voltage is exactly equal to the amount of current flowing across the neuronal membrane. This allows us to directly measure these membrane currents, and indicates how membrane potential influences ionic current flow across the membrane.

Question 5

Is the voltage clamp method still used today?

Answer 5

Yes! The voltage clamp method remains widely used to study ionic currents in neurons and other cells. The most popular contemporary version of this approach is the patch clamp technique, a method that can be applied to virtually any cell and has a resolution high enough to measure the minute electrical currrents flowing through single ion channels.

Question 6

Using the patch clamp method, Hodgkin and Huxley were able to measure the membrane current (movement of ions across the membrane) during different experimentally controlled membrane potentials. What did they notice about the membrane current when they depolarized the cell?

Answer 6

After the induced capacitive current, they noticed an early inward current and a delayed outward current.

Question 7

How did Hodgkin and Huxley figure out what ions were responsible for the early membrane current during a depolarization?

Answer 7

1. When clamped at +52mV, there was no early current.
2. Knowing the concentrations of Na⁺ on both sides of the membrane, the Nernst equation predicts equilibrium ( [Na⁺]_in == [Na⁺]_out ) at +55mV.
3. When Na⁺ is removed from the external environment ( [Na⁺]_in >> [Na⁺]_out ), the early current is reversed and indicates an outward current.

Question 8

How did Hodgkin and Huxley figure out which ion was responsible for the delayed current?

Answer 8

1. Removal of Na⁺ had little effect on the outward current.
2. Loading the neuron with radioactive K⁺ enables us to observe an efflux during depolarization that is closely correlated with the magnitude of the late outward current.

Question 9

Summarizing Hodgkin and Huxley’s work: experiments show that changing the membrane potential to a level more positive than the resting potential produces two effects. Which?

Answer 9

1. An early influx of Na⁺ into the neuron.

Followed by..

2. A delayed efflux of K^+.

Question 10

“The permeability of Na⁺ and K⁺ is caused by the same permeability pathway”. Truth of flase?

Answer 10

False. Pharmacological studies of dugs that specifically affect the functioning of neurons (tetrodotoxin, tetraethylammonium) have found that the potassium and sodium currents can be blocked independently. This is strong evidence that the permeability of these ions are governed by different pathways.

Question 11

What causes the undershoot, aka the natural hyperpolarization at the end of the action potential?

Answer 11

The undershoot is caused by a still higher K⁺ conductance, aka a higher permeability to potassium ions than during resting potential, and a more negative equilibrium potential of potassium than the resting potential. Also the persistence of Na⁺ conductance inactivation.

Question 12

What is the axon’s conduction velocity?

Answer 12

THe speed at which the action potential moves along the axon.

Question 13

Mention two processes that affect action potential conduction speeds.

Answer 13

1. The passive current flow on the inside of the membrane.
2. The active current flow between the inner and outer membrane.

Question 14

Two ways of improving passive current flow are..

Answer 14

1. To increase the diameter of the axon, which effectively decreases the internal resistance to passive current flow.
2. To reduce leak out of the axon by insulating the axonal membrane.

Question 15

What is myelination?

Answer 15

Myelination is a process by which oligondendrocytes in the central nervous system (and Schwann cells in the peripheral nervous system) wrap the axon in myelin, which consists of multiple layers of closely opposed glial membranes.

Question 16

Unmyelinated axon conduction velocities range from about X m/s to Y m/s.

Answer 16

0.5 to 10 meters per second.

Question 17

Myelinated axons can conduct at velocities of up to X m/s, Y times faster than the fastest unmyelinated axons.

Answer 17

Myelinated axons can conduct at velocities of up to 150 m/s, 15 times faster than the fastest unmyelinated axons.

Question 18

Why are myelinated axons faster?

Answer 18

Because the time-consuming process of action potential generation occurs only at specific points along the axon.

Question 19

What are nodes of Ranvier?

Answer 19

Nodes of Ranvier are unmyelinated gaps on a myelinated axon where action potential generation occurs.

Question 20

.. is a disease of the central nervous system characterized by a variety of clinical problems that arise from demyelination and inflammation along axonal pathways.

Answer 20

Multiple sclerosis (MS).

Question 21

Multiple sclerosis (MS) typically manifests at what age?

Answer 21

Between the ages 20 and 40.

Question 22

What clinical course is expected for patients with multiple sclerosis?

Answer 22

The clinical course ranges from patients with no persistent neurological loss, some of whom experience only occasional later symptoms, to other who progressively deteriorate as a result of extensive and relentless central nervous system involvement.

Question 23

What determines the symptoms of multiple sclerosis?

Answer 23

The signs and symptoms of MS are determined by the location of the affected regions.

Question 24

How is multiple sclerosis diagnosed?

Answer 24

It is a difficult disease to diagnose, generally relying on the presence of a neurological problem that remits, only to return at an unrelated site. Confirmation can sometimes be obtained from MRI or fMRI.

Question 25

Multiple sclerosis may have effects that extend beyond loss of the myelin sheath. Which?

Answer 25

It is clear that some axons are actually destroyed, probably as a result of inflammatory processes in the overlying myelin and/or loss of trophic support of the axon by oligodendrocytes. This supports the leading hypothesis that MS is an autoimmune disease.

Question 26

What protein has been the focus of study in recent research on multiple sclerosis?

Answer 26

contactin-2.

Question 27

What is contactin-2 and how has it been used to explain multiple sclerosis?

Answer 27

Contactin-2 is a protein found on glia and axons at the node of Ranvier. A possible explanation of the human disease is that a genetically susceptible individual becomes transiently infected (by a minor viral illess, for example) with a microorganism that expresses a molecule structurally similar to contactin-2 or some other component of myelin. An immune response to this antigen is mounted to attack the invader, but the failure of the immune system to discriminate between the foreign protein and self results in destruction of otherwise normal myelin.

Question 28

The most popular hypothesis to multiple sclerosis is of MS as an autoimmune disease. What is an alternative hypothesis?

Answer 28

An alternative hypothesis is that MS is caused by a persistent infection by a virus or other microorganism. This is mostly because the symptoms of rapidly advancing MS is similar to that of tropical spastic paraparesis (TSP), which is known to be caused by a virus.

Question 29

Concluding words on multiple sclerosis. Which hypothesis for how it is caused is most likely?

Answer 29

“Despite periodic reports of a virus associated with MS, convincing evidence has not been forhtcoming. In sum, despite the benefits to some patients of immunomodulatory therapies, the diagnosis and treatment of multiple sclerosis remains a daunting clinical challenge”.