C1. Nervous System Physiology: Action Potential

Nervous System Physiology

Major Organs of the Nervous System

  • Brain
  • Spinal cord
  • Peripheral nerves
  • Sense organs

Functions of the Nervous System

  • Directs immediate responses to stimuli.
  • Coordinates or moderates activities of other organ systems.
  • Provides and interprets sensory information about external conditions.

Physiology Road Map

  • Organ System: Nervous system
  • Level of Organization: Cellular & molecular

Learning Outcomes

  • Compare and contrast components of axonal membrane: Na^+/K^+ pump, Na^+ and K^+ voltage-gated ion channels, Na^+ and K^+ leak channels.
  • Compare and contrast activation and inactivation gates of voltage-gated Na^+ ion channels.
  • Sequence membrane potential, ion channel activity, and ion flow during an action potential.
  • Diagram voltage-time graphs during graded potentials and action potentials.
  • Compare and contrast absolute and relative refractory period.
  • Compare and contrast types of conduction.
  • Compare and contrast factors affecting conduction.

Lecture Outline

  • I. Graded Potentials
  • II. Action Potential
  • III. Conduction of Action Potentials
  • IV. Factors Affecting AP Conduction

Neuron Excitability at Rest

  • A neuron at rest is excitable.
  • At rest, both electrical and chemical driving forces want to "push" Na^+ into the neuron.
    • Large negative F_{ion} = -120.
  • At rest, neurons are not very permeable to Na^+.

Types of Voltage Changes Across the Membrane

  1. Graded potential
  2. Action potential: triggered by large depolarizing graded potential(s).

Graded Potentials

  • Graded Potentials: variable-strength signals that travel over a short distance.
    1. Lose strength as they move through the cell.
    2. Mainly occur at dendrites, cell body, axon terminals.

Graded Potential Size

  • Graded potential size is proportional to the size of the triggering event.
    • Amplitude: height/size of hyperpolarization or depolarization.
    • Determined by # of ions crossing the membrane and # of open ion channels.

Size of Graded Potentials

  • Produced by local current flow: ion movement at one region of the membrane.
    • Larger local current flow → larger graded potential.
  • Decrease in strength as they travel through the cytoplasm.
    • Closer to region of influx/efflux → larger graded potential.

Graded Potentials Decay

  • Electrical Resistance Review

Subthreshold Graded Potential

  • A graded potential starts above threshold (T) at its initiation point but decreases in strength as it travels through the cell body.
  • At the trigger zone, it is below threshold and, therefore, does not initiate an action potential.

Graded Potentials Decay - Voltage Decay

  1. Cytoplasm resistance (R_i)
    • A neuron with high R_i has many organelles blocking ion flow.
    • High opposition to current flow through cytoplasm → voltage decay.
  2. Membrane resistance (R_m)
    • A neuron with low R_m has many open leak channels on the membrane, so ions diffuse into ECF.
    • Low opposition to current flow through the membrane → voltage decay.

Graded Potentials Trigger Action Potential - Threshold

  • If and only if:
    1. Vm reaches threshold potential (V{threshold}): membrane potential required to trigger AP (often -50 to -55 mV).
    2. At the Trigger Zone: integrating center of the neuron.
      • Structure: region of the axon hillock with a high concentration of voltage-gated (V-G) Na^+ channels.

Graded Potentials Trigger Action Potential - All-or-None Phenomenon

  • All-or-None Phenomenon: APs either occur and reach maximum depolarization, or do not occur at all.
    • Subthreshold graded potentials do not trigger AP.
    • Suprathreshold graded potentials ALWAYS trigger AP.

Action Potential

  • Action Potential: “spike” or “firing”, electrical signals of uniform strength that travel from trigger zone to the end of the axon.
  • Produced by a coordinated sequence of voltage-gated ion channels opening/closing.

Voltage-Gated Ion Channels

  • Voltage-gated (V-G) ion channels open/close in response to changes in membrane potential.
    • Open in sequence as electrical current travels down the axon.

Voltage-Gated Na^+ Channels

  • Voltage-gated Na^+ channels have two gates:
    1. Activation gate: suprathreshold depolarization → rapidly open.
    2. Inactivation gate: closes channel 0.5 ms after activation.
  • Two gates allow for three states:
    1. Closed: activation gate closed, inactivation gate open.
    2. Open: activation gate open, inactivation gate open.
    3. Inactivated: inactivation gate closed, activation gate open.

Voltage-Gated K^+ Channels

  • Voltage-gated K^+ channels have one gate and two states.
    • Activation gate: suprathreshold depolarization → open SLOWLY.
    • Two states:
      1. Closed
      2. Open at the peak of the action potential.

Sequencing Action Potential

  1. RMP: -70 mV
  2. Stimulus
  3. Suprathreshold, graded depolarization reaches trigger zone → V-G Na^+ activation gates open
  4. Rising Phase: rapid, large depolarization
    • More V-G Na^+ activation gates open
    • I_{Na^+} from ECF→ ICF
  5. Peak: max V_m, ~+30 mV
    • V-G Na^+ channel inactivation gates close
    • F{Na^+} remains until E{Na^+} of +60 mV
    • V-G K^+ channels open
  6. Falling Phase:
    • Repolarization: rapid decline in membrane potential, toward RMP
    • I_{K^+} from ICF→ ECF
  7. Undershoot: hyperpolarization
    • F{K^+} remains until E{K^+} of -90 mV
    • V-G K^+ channels & leak channels remain open → additional K^+ leaves cell
    • V_m falls below RMP
  8. V-G K^+ channels close
    • Na^+ leaks into ECF
    • Na^+/K^+ pump pumps -> RMP

AP Phases Generated by Voltage-Gated Ion Channels

  • Activity dependent on V_m

  • Depolarization

    1. Na^+ channel activation
    2. Large F_{Na+}
    3. Na^+ influx = depolarization

  • Repolarization

    1. Na^+ channel inactivation
      • Time-dependent, very fast
    2. K^+ channel activation
      • Voltage-dependent
    3. K^+ flows out = rapid repolarization

  • Hyperpolarizing Afterpotential

    1. Excess I_k
      • Voltage-dependent

  • Return to V_{rest}

    1. K^+ channel deactivation
    2. Na^+ channel deactivation
    3. Vm = Vr (when leak channels are only activated channels)

  • Very small # of ions cross during an AP, don't affect gradients.

  • Repolarization is not due to ATPase pumps (too slow)

  • If block K^+ channels:

    • Still get repolarization as ions diffuse away from the membrane (much slower repolarization, long duration AP)

Initiation of Action Potential

  • Can be thought of as a feedback loop.

Conduction of Action Potential

  • High-speed movement of AP down the axon.
  • Neurons that make up the sciatic nerve can be >1 m long

Mechanism of AP Conduction

  1. APs are regenerated and do not diminish in strength as they travel.
  2. AP occurs at axon hillock
  3. Depolarization peak > V_{threshold}, which triggers V-G Na^+ channels to open in adjacent axon segment
  4. AP in adjacent axon segment

Positive Feedback Loop

  • Na^+ entry during an action potential creates a positive feedback loop.
  • The positive feedback loop stops when the Na^+ channel inactivation gates close.

Absolute Refractory Period

  • Ensures APs travel in one direction.
  • Retrograde current flow: depolarization will occur in previously firing regions but cannot trigger AP.
  • Ensures APs cannot overlap or travel backwards.
  • 1-2 ms after the start of AP, during which AP cannot be triggered no matter the size of the stimulus.

Mechanism

  • VG Na^+ channels inactivate at the AP peak.
  • Repolarization must reactivate VG Na^+ channel before another AP can occur.

Relative Refractory Period

  • Limits the rate of APs.
  • 2 ms following absolute refractory period, during which only strong stimuli can trigger AP.
  • Function: limits rate of signals transmitted down neuron.

Mechanisms

  • Two mechanisms increase threshold (closer to 0 mV):

    1. Some, but not all V-G Na^+ channel gates reset
    2. V-G K^+ channels (plus the leak channels) are still open

  • AP only produced during relative refractory period when the stimulus is sufficient to:

    1. Open available (reactivated) V-G Na^+ channels AND
    2. Overcome loss of K^+

Refractory Periods Comparison

  • Absolute Refractory Period
    1. No second AP possible (even with a large stimulus)
    2. Caused by Na^+ channels still being inactivated (removal of inactivation requires repolarization)
  • Relative Refractory Period
    1. Second AP possible but requires a larger stimulus
    2. Caused by some K^+ channels still being activated (so requires more stimulus to reach threshold)
  • The absolute refractory period sets the maximum AP frequency

Effects of Calcium

  • High external calcium:
    • Increased V_T
    • Decreased reflexes
    • Decreased memory
    • Depression
    • Decreased Activation
    • Decreased slope of depolarization
    • Decreased AP Peak
  • Low external calcium:
    • Increased reflexes
    • Spasms
    • Seizures
    • Hyperexcitable

Factors Affecting Conduction

  • Axon size directly proportional to conduction velocity
    • Larger axon diameter → Lower R_i → Faster conduction
    • Squid giant axon conduction velocity: ~25 m/s
    • Non-giant axons: 0.5-2 m/s
  • Membrane resistance directly proportional to conduction velocity
    • Less permeable membrane → Higher R_m → Faster conduction
    • Myelination reduces current leak and increases R_m

Types of AP Conduction

  1. Continuous conduction: repeated APs down the length of the axon
    • Unmyelinated axons
    • Slow, energetically expensive conduction
  2. Saltatory conduction: “jumping” AP down the length of the axon
    • Myelin sheath: layers of insulating membrane, prevents ion flow from cytoplasm
    • Nodes of Ranvier: Unmyelinated sites with high concentration of V-G Na^+ channels
    • Demyelinating diseases (i.e. MS & Guillain-Barre) slow conduction