Neurophysiology - RMP and Action Potentials

Question 1

What is membrane potential of a cell

Answer 1

The electrical voltage of its interior relative to its exterior

Question 2

What is resting membrane potential, normal RMP in excitable and non-excitable tissue and what is an action potential

Answer 2

Resting Membrane Potential (RMP) is the electrical voltage difference of a cell membrane of its interior relative to its exterior at rest.

Normally

1. Nerve : -70mV
2. Cardiac and Skeletal muscle: - 90mV
3. Non-excitable cells: -30 mV
4. Small intestine: -40 –> -70 mV

An action potential is a transient change in membrane potential from RMP to a positive value. The cell membrane is then describe as being depolarized.

Question 3

Under what circumstances will there be a negative membrane potential

Under what circumstances will there be a positive membrane potential

Answer 3

Negative: When there are more positively charged ions outside the cell versus inside the cell

Positive: When there are more positively charged ions inside the cell versus outside the cell.

Question 4

Why is there a charge difference between the inside and the outside of the cell creating a membrane potential?

Answer 4

Variation in the distributions of ions across the cell membrane affected by:

1. Selective permeability of cell membrane
2. Negatively charged intracellular proteins
   - bind cations and repel anions

Question 5

Which three major ions influence the resting membrane potential

Answer 5

1. K+
2. Na+
3. Cl-

Question 6

Compare the intracellular and extracellular concentrations of Na and K and indicate why these different concentrations exist

Answer 6

The different concentrations are established by the Na/K ATPase pump.

K+
Inside 150 mmol/L
Outside 5 mmol/L
1. Phospholipid bilayer is impermeable to charged K+
2. K+ leak channels exist that permit K+ to pass down conc. gradient: from ICF to ECF

Na+
Inside 20mmol/L
Outside 140 mmol/L
1. Phospholipid bilayer is impermeable to Na+
2. At RMP Na channels are closed leaving the resting cell membrane impermeable to Na

Question 7

How do intracellular Cl- concentrations affect membrane potential

Answer 7

They don’t. Membrane potential passively influences Cl- movement.

Question 8

What does the Nernst equation calculate?

Answer 8

For a particular membrane-permeant ion X (e.g. K+), the Nernst equation calculates the contribution that that ion makes to the overall resting membrane potential at X’s electrochemical equilibrium

Question 9

Write the Nernst Equation and state what each variable and symbol stand for

Answer 9

Ex = RT ln [X]o
__ ___

     zF           [X]i

Ex: Nernst potential for a particular ion (mV)
R: Universal gas constant (8.314 J/(K mol)
T: Absolute temperature (K)
F: Faraday constant (the electrical charge per mol of electrons 96500C/mol)
[X]o: Ion concentration outside
[X]i: ion concentration inside

ln = log e (natural logarithm)

Question 10

What is the Goldman-Hodgkin-Katz equation?

Answer 10

The equation used to calculate the membrane resting potential taking into consideration the intracellular and extracellular concentrations of Na, K and Cl- as well as the membrane permeability to these contributing ions.

Question 11

How does hyperkalaemia affect nerve conduction

Answer 11

PRINCIPLE: THE MORE POTASSIUM THAT LEAKS FROM ICF TO ECF THE MORE DEPOLARIZED THE RMP.

Hyperkalaemia –> reduced K+ leakage into ECF (reduced gradient) i.e. Nernst potential for K+ (the determinant of RMP) goes from -90 mV to -80 mV (depolarised). –> closer to threshold potential –> spontaneous generation of action potentials more likely –> VF etc.

Question 12

How does hypokalaemia affect nerve conduction

Answer 12

PRINCIPLE: THE MORE POTASSIUM THAT LEAKS FROM ICF TO ECF THE MORE DEPOLARIZED THE RMP.

Hypokalaemia –> Increased K+ leakage into ECF (increased gradient) i.e. Nernst potential for K+ -90 –> -100 mV which is hyperpolarized –> further from threshold potential –> more difficult to generate and propagate action potentials –> Muscular weakness and ECG changes.

Question 13

How do hyper and hypoNa+ affect nerve conduction. Explain seizures in severe hyponatraemia

Answer 13

As the cell membrane is relatively impermeable to Na –> changes to [Na] have minimal effect on RMP.

In severe hyponatraemia reduced ECF osmolarity causes cells to swell –> dilution of IC K+ –> reduced outward movement of K into ECF and depolarization of RMP –> closure to threshold –> increased spontaneous initiation and propagation of action potentials –> seizures.

Question 14

Explain the mechanism of tetany and paraesthesias in hypocalcaemia

Answer 14

Ca++ maintains normal function of Na+ channels.

HypoCa+ –> activation Na channels –> more negative threshold potential (closer to RMP) –> spontaneous depolarization of neurons –> tetany and paraethesias

Question 15

Explain why Ca++ is given for cardioprotection in hyperkalaemia?

Answer 15

Calcium has a membrane stabilizing effect due to the ‘surface charge hypothesis’.

Ca+ binds to the outside of the cell attached to glycoproteins –> increasing positive charge on the extracellular side of the membrane (impermeable to Ca+) –> hyperpolarization of RMP.

Question 16

Define an action potential

Answer 16

TRANSIENT REVERSAL of membrane potential that occurs in EXCITABLE CELLS (neurons, muscle cells, endocrine cells).

‘ALL OR NOTHING EVENT’ i.e. only if the stimulus cause membrane depolarisation that breaches the AP threshold potential.

AP’s allow RAPID SIGNALLING within excitable cells over relatively LONG DISTANCE.

Question 17

Which part of the neuron does the action potential start and why

Answer 17

At the axon hilock as it has the lowest threshold owing to its high density of voltage-gated Na channels

Question 18

What is the Nernst equilibrium potential for Na and K. Contrast these values with the voltage of the RMP and the threshold potential

Answer 18

Na is + 55mV
K is - 90 mV

RMP is -70 mV (close to K due to K leak channels)
Threshold is -55 mV

Question 19

Why is there no action potential if the threshold potential is not reached

Answer 19

Stimulus too small so Na influx is exceeded by K + efflux through K+ leak channels

Question 20

What causes the initial upstroke of the action potential in nerve cells and what terminates this upstroke

Answer 20

Large stimulus –> breach threshold potential –> opening Na channels –> depolarization –> further opening of Na channels –> depolarization –>

However, when the AP reaches its theoretical maximum

1. Inactivation of Na channels occurs
2. Delayed opening of Voltage gated K channels –> K + efflux –> repolarization

Question 21

What causes after-hyperpolarization

Answer 21

Gradual closure of Voltage gated potassium channels

Question 22

Draw the action potential

Answer 22

Page 222 chambers

Question 23

How is the AP propagated

Answer 23

1. IC surface of membrane normally negatively charged
2. Following AP a portion of the cell membrane depolarizes
3. IC surface becomes positivel charged
4. ion movement at verge of positively charge IC membrane surface results in depolarization of neighbouring portions of the membrane and propagation

Question 24

What factors affect the velocity of the action potential conduction

Answer 24

1. AXON DIAMETER: wider –> lower resistance
2. MYELIN
   - –> Transmembrane resistance increased –> faster conduction
   - –> Transmembrane capacitance –> decreased –> faster conduction
   - –> Nodes of Ranvier and saltatory conduction –> faster conduction
3. TEMPERATURE: Increase temperature –> more rapid opening of Na channels –> faster velocity

Question 25

What cells produce myelin in the CNS vs PNS

Answer 25

CNS –> oligodendrocytes

PNS –> Schwann cells

Question 26

Summarise the effects of myelin on action potential propagation

Answer 26

1. Increased transmembrane resistance (harder for current to escape nerve into ECF)
2. Reduced membrane capacitance (easier to alter polarity)
3. Saltatory conduction: nodes of Ranvier (densely packed with Na channels): AP ‘jumps’ node to node

Question 27

What is the conduction velocity of an AP in a myelinated vs an unmyelinated neuron

Answer 27

Unmyelinated: 2 m/s

Myelinated: 120 m/s

Question 28

What are two important autoimmune disease that lead to destruction of the myelin sheath in the CNS and the PNS

Answer 28

CNS - Multiple Sclerosis

PNS - Guillain-Barre Syndrome

Question 29

What is the difference in AP conduction in an unmyelinated versus a demyelinated (MS and GBS) neuron

Answer 29

Demyelinated –> demyelinated neurons have densly packed Na channels at the nodes of Ranvier but the demyelinated portion have inadequate sodium channels to reliably conduct AP –> failure of conduction

Unmyelinated: AP conducted slower but reliably as there are adequate Na channels along the length

Question 30

Describe the functional classification of nerve fibres

Include diameter/speed/myelination/ sub classification and anatomical location

Answer 30

A alpha - EXTRAFUSAL MOTOR - 20um - 120m/s - myelinated - Least affected by local anaesthetic (LA)
A alpha - Sensory 1a PROPRIO. - 20um - 120m/s - myelinated - Mild affect LA
A alpha - Sensory 1b PROPRIO. - 20um - 120m/s - myelinated - Mild affect LA

A beta: Sensory II - touch/pressure -10um - 60m/s - myelinated - Mild affect LA
A gamma: INTRAFUSAL MOTOR - 5 um - 30 m/s - myelinated - Mild LA affect
A delta: Sensory III - pain/temp - 5 um - 30 m/s - myelinated - Moderate LA effect

B - Preganglionic ANS fibres - <3 um - 10 m/s - myelinated - Severe affect LA

C - Dorsal root) - Sensory IV - Pain/temp/touch - 1 um - 2 m/s - unmyelinated - Severe affect LA

C - Postganglionic SNS - 1 um - 2 m/s - unmyelinated - Severe affect LA

Question 31

Explain the mechanism of action of local anaesthetics

Answer 31

1. Unionized (bases ionize at pH below pKa) portion move into neuron
2. Ionized within neuron (lower IC pH) –> cannot diffuse out into ECF
3. Block inner surface V gated Na channels in their refractory state
4. Prolongation of absolute refractory period

Question 32

Which nerve types are most to least sensitive to local anaesthetics and what are the clinical effects of this

Answer 32

Small diameter and myelinated fibres

Overall clinical effects: most sensitive to least:

1. A delta (fast pain and thermo) (Intermediate thickness + myelinated)
2. B fibres (Preganglionic ANS)
3. A alpha (extrafusal motor), A beta (touch/pressure/proprio), A gamma (intrafusal motor)
4. C fibres (slow pain) (most resistant)

Question 33

What is the absolute and relative refractory period

Answer 33

Absolute refractory period is the period immediately after and action potential where a further action potential cannot be triggered regardless of the size of the stimulus.
- inactivated v gated sodium channels

Relative refractory period is the period after the absolute refractory period where only a stimulus of increased size can trigger a further action potential.
- Both leak K channels and V gated K channels are open –> therefore a greater stimulus is required to counteract the increased K+ efflux.

Question 34

Why is the refractory period important?

Answer 34

1. Ensure unidirectional propagation of action potentials

2. Limits frequency of APs generated in a given time period