A rapid change in the membrane potential depolarization followed by a return to the resting membrane potential.

Function of Action Potentials        

1.  Basis of signal transmission of excitable cells (nerve, muscle)

      2.  Initiation of muscle contraction

True or false:

Action potentials are the same size and shape along the whole length of a nerve or muscle cell but vary in size and shape between cells. 

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Note:

resting potential, threshold, depolarizing phase, peak, overshoot, repolarizing phase, and hyperpolarizing phase (used to be undershoot)

What are some experimental observations of membrane potentials?

1  What is the resting membrane potential (in mV)?

2.  What does passing a small current into the cell do to the membrane potential?

3.  What does passing a small current out of the cell do to the membrane potential?

1.  Em is about -90mV at rest

2.  Causes hyperpolarization (-90 to -100mV)

3.  Causes depolarization (-90 to -70 mV)

True or false:

1. Electronic potentials are proportional to the stimulus

2. An action potential will occur regardless of the amount of depolarization.

1. True

2. False, an action potential occurs if the membrane potential reaches threshold.

Define:

1. length constant and typically values

True of false:

2.  A membrane with a long length constant will have more current decay than an identical membrane with a short length constant.

3.  The size of the voltage response decreases exponentially with distance from the point of current passage.

1.  Length constant = The distance it takes for the voltage response to decay about 37% of its original size

2.  False, A membrane with a long length constant will have less current decay than an identical membrane with a short length constant.

3. True

Size and shape of APs

      1.  All-or-none response.

      2.  Threshold

      3.  Overshoot

      4.  Hyperpolarizing afterpotential

1.  All-or-none response - actively propagate along a cell membrane without decrement once they pass threshold.  If they don't pass threshold, an AP won't occur at all.

      2.  Threshold –the membrane potential that is sufficient for the triggering of an action potential (-60 mV).

      3.  Overshoot – value of the membrane potential that is reached at the peak of the action potential (+50 mV).

      4.  Hyperpolarizing afterpotential – transient hyperpolarization (below resting potential) after the repolarization phase of the action potential.

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1. Absolute refractory period: A second response is not possible regardless of strength or duration of the stimulus.  The absolute refractory period is due to voltage-dependent inactivation of many Na⁺ channels.  An action potential cannot be generated no matter how strongly the cell is stimulated because the Na channels can’t open.

2.  Relative refractory period: A second response can be elicited, but at a greater strength and/or duration. Relative Refractory Period – some Na⁺ channels are voltage inactivated and some of the K⁺ channels are open, both of which make it more difficult to depolarize the membrane to threshold.

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The depolarization stage has an increase in sodium (Na) conductance and the membrane potential is driven toward the equilibrium for sodium.

Then the potassium (K) conductance increases more slowly and the membrane potential is driven toward the equilibrium for potassium as the sodium channels are inactivated.

1. Tetraethylammonium (TEA)

2. Tetrodotoxin and Saxitoxin (block sodium current) or Veratridine (opens channels to sodium)

Sodium (Na) channels:

1.  Are they gated?

2.  How many channels are open at rest (few or a lot)?

3.  How many potassium (K) channels are open at rest?

4.  What does depolarization do to the sodium (Na) channels?

1.  Yes, sodium (Na) are gated

2.  Very few sodium (Na) channels are open at rest

3.  A large fraction of potassium (K) channels are open at rest - which is why the resting membrane potential is -70mV, close to the K equilibrium of -100mV

4.  Depolarization increases the probability of a sodium (Na) channel being open.

Voltage-gated Na channels

1. Describe role in nerve and muscle membranes

2.  Describe the activation gate

3. Describe the inactivation gate

      1.  Sodium (Na) channels are responsible for the electrical excitability of both nerve and muscle membranes.

      2.  Activation gate – controls the rate and voltage dependence of permeability increase following depolarization.  Charge within the membrane is rearranged when voltage-gated Na+ channels open (↑open channels = ↑permeability).  Permeability is the “leakiness” of membrane to a particular ion.

            3.  Inactivation gate – controls the rate and voltage dependence of subsequent return of permeability to the resting level (blocks ion movement) during a maintained depolarization.

Sodium (Na) channel

1.  Oragnize the ion selectivity for the channel (Rb, K, Li, Na, and Cs)

2.  What's the unit conductance?

3. How many subunits make up the channel?

4. What are the functional portions of the channel?

1.  Na⁺ = Li⁺ > K⁺ > Rb⁺ > Cs⁺ 

2.  Unit conductance 12-18 pS = 10⁷ ions/sec/channel.

3.  Integral membrane glycoprotein complex (- 316,000 Da)

α subunit – 270,000 Da

β₁ subunit – 39,000 Da

β₂ subunit – 37,000 Da

4.  Voltage sensor in the S4 region of the α unit and the pore region is between S5 and S6.

The β₁, β₂, and α unit are glycosylated

The α unit has four domains that are homologous to a single subunit of the voltage-gated K ghannel. 

The α unit has a site of cAMP-dependent protein phosphorylation

Voltage-gated potassium (K) channel

1.  How many subunits does K have?

2. Describe the functional portions of the channel

1.  It has 4 indentical α subunits (4 separate proteins) and 1 cytoplasmic β subunit.

2. Voltage sensor in the S4 region of the α unit and the pore region is between S5 and S6.

The β and α subunits are glycosylated

Conduction of Action Potentials

1.  What does velocity depend on?

2.  What does speed of conduction depend on?

3.  What does resistance to current flow depend on?

4. How does fiber size effect conduction velocity?

5.  What is the effect of myelination?

6.  What is the function of the myelin sheath?

1. Velocity of conduction depends on the rate at which the membrane adjacent to the point of stimulation can be discharged to threshold.  This area then fires an action potential and local current flows to            discharge the next area.

      2.   Speed of electronic conduction depends on the passive responses of the membrane.

 3.   Resistance to current flow depends on the resistance to current flow across the membrane (r_m) and the resistance to longitudinal current flow along the cytoplasm(r_in).

   4.   Effect of fiber size on conduction velocity.  Larger diameter fibers – decreased resistance to conduction – action potentials travel faster.

5.   Effect of myelination on conduction velocity.  Squid axon (500 micrometers): 25m/sec. Human nerve (10 micrometers ) 0.5m/sec, but actually 50 m/sec due to myelin.

     6.   The myelin sheath increases the velocity of action potential by (1) increasing the length constant of the axon, (2) decreasing the capacitance of the axon, and (3) restricting the generation of action potentials to the nodes of Ranvier.

1.   Paralysis due to electrical inexcitability of muscle surface membrane.

2.   Attacks can occur from less than an hour to several days.

3.   Weakness can be localized or generalized.

 4.   Muscle fibers become inexcitable to either direct or indirect stimulation during attacks.

 5.   Rest after exercise tends to provoke weakness of the muscles that have been exercised but continued mild exercise may abort the attacks. 

 6.   Exposure to the cold may provoke weakness in the primary forms of the disease.

 7.   Complete recovery usually occurs after initial attacks.

 8.   Permanent weakness and irreversible pathological changes in muscle develop after repeated attacks of the primary forms of this disease. 

 9.   There is a depolarization of the muscle surface membrane during paralysis and the action potential fails because the sodium channel is abnormally sensitive to inactivation even by minor membrane depolarization.

1.  Hyperkalemic periodic paralysis

involves a Thr-Met change in S5 of domain II or

Met-Val change in S6 of domain IV

2.  Paramyotonia congenita

involves a Gly-Val or Thr-Met change in the

intracellular segment between domains III and IV or

a Leu-Arg or Arg-His/Cys change in the

S3 or S4 of domain IV

Describe Hyperkalemic Periodic Paralysis

1.  Genetics (autosomal or X linked, dominant or recessive)

2.  Proposed mechanism of disease

3.  Patients dietary restriciton

1.  Autosomal dominant disorder which results in painful spontaneous muscle contractions, episodic electrical inexcitability and paralysis of skeletal muscle due to elevated serum potassium.

2. Proposed mechanism   

            - Initially, long lasting action potentials → increase in K⁺ efflux → increase extracellular K⁺ → depolarization of muscle cells → closer to threshold → spontaneous action potentials and contractions

            - Later cells accommodate → voltage inactivation Na channels → no action potential → paralysis

3.  Patients advised not to eat high potassium foods

Define:

1.  Accommodation

2. Local response

3.  Voltage clamp technique

1.  An increase in the threshold for an action potential that occurs in some neurons during a slowly developing or prolonged depolarization. The result is that only a few action potentials are generated during prolonged depolarization above the normal threshold level.

2. Depolarization or hyperpolarization at the membrane.

3.  Electronic feedback is used to set Em at whatever level the experimenter desires.  The voltage clamp amplifier then keeps the Em at the level and measures the net ionic current that flows across the membrane.

If you slowly depolarize the membrane in an excitable cell you do not initiate an action potential because of:

 A. Absolute refractory period

 B. Accommodation

 C. Facilitation

 D. Hyperpolarization

 E. Relative refractory period

A 28-year-old woman has a history of paralysis following meals with high potassium content.  Electrophysiological studies on a muscle biopsy from this patient indicated abnormal ion channel inactivation.  Which muscle ion channel is likely altered in this patient?

 A. Voltage-gated calcium channel

 B. Voltage-gated sodium channel

 C. Voltage-gated potassium channel

 D. Calcium release channel

 E. Presynaptic calcium channel

A 25-year old female undergoes electromyographic testing as part of the evaluation for her profound muscle weakness.  She is found to have a very prolonged relative refractory period.  Which of the following channel properties controls the relative refractory period.

A. Sodium channel inactivation

B. Sodium channel activation

C. Potassium channel activation

D. Potassium channel inactivation

E. Calcium channel activation