Neuronal Membrane Potentials & Action Potentials Comprehensive Notes

Changes in Membrane Potential

• Membrane potential can RISE (depolarize) or FALL (hyperpolarize)
• Caused by temporary changes in membrane PERMEABILITY
  • Temporary → due to OPENING / CLOSING of specific ion channels
• Ion channels regulate ion movement → therefore control membrane voltage

Ion Channels That Shape Membrane Potential

• Overall permeability to $\text{Na}^+$ and $\text{K}^+$ sets the moment-to-moment value of the membrane potential (MP)
• Two major functional types
  • Passive ("leak") channels
  • Always OPEN
  • Permeability varies with conditions (e.g., temperature, membrane stretch)
  • Fundamental for establishing RESTING MP
  • Active ("gated") channels
  • OPEN / CLOSE in response to specific stimuli
  • At resting MP most gated channels are CLOSED
  • Each gated channel can occupy THREE states
    1. OPEN (activated)
    2. CLOSED but capable of opening
    3. CLOSED and incapable of opening (inactivated)

Three Classes of Gated Channels

1. Chemically (ligand) gated
2. Voltage-gated
3. Mechanically gated

Chemically Gated Channels (Ligand-Gated)

• OPEN / CLOSE when specific chemical (e.g., ACh) binds to its receptor site
• Typical locations: neuronal cell bodies & dendrites, neuromuscular junctions (NMJ)
• Example: ACh-gated $\text{Na}^+$ channel
  • RESTING: channel closed
  • ACh binds → channel opens → $\text{Na}^+$ influx → local depolarization

Voltage-Gated Channels

• Triggered by changes in local MP
• Exist in EXCITABLE MEMBRANES (neuronal axons, skeletal muscle sarcolemma, cardiac myocytes)
• Structure/function highlights
  • ACTIVATION GATE opens rapidly once threshold reached ⇒ ions enter
  • INACTIVATION GATE closes shortly after ⇒ stops ion flow
• Example voltage-gated $\text{Na}^+$ channel behaviour
  • $-70\,\text{mV}$ (rest) → closed
  • $-60\,\text{mV}$ (threshold) → activation gate opens (channel "open")
  • $+30\,\text{mV}$ → inactivation gate closes (channel "inactivated")

Mechanically Gated Channels

• Respond to PHYSICAL membrane distortion (stretch, pressure, vibration)
• Localized on dendrites of SENSORY (afferent) neurons (e.g., cutaneous mechanoreceptors)
• Deformation opens pore → ion flux → generator (graded) potential

From Graded Potentials to Action Potentials

• Presynaptic stimuli → graded potentials on dendrites / soma
• If graded depolarization large enough at AXON HILLOCK (trigger zone) to reach THRESHOLD (≈ $-60 \text{ to } -55 \text{ mV}$) → ACTION POTENTIAL (AP) starts
• AP travels along axon → triggers neurotransmitter release at synapse → postsynaptic graded potentials → information processing cycles

Key Features of Graded Potentials (Table 12-2)

1. Maximal effect at SITE OF STIMULATION; magnitude decays with distance
2. Spread PASSIVELY via local currents
3. May be DEPOLARIZING OR HYPERPOLARIZING depending on channel opened
   • Open $\text{Na}^+$ → depolarize
   • Open $\text{K}^+$ → hyperpolarize
4. Magnitude proportional to stimulus strength (graded)

Action Potentials: Definition & Necessity

• Ion-based electrical signals produced by every plasma membrane but CRITICAL for neurons & muscle fibers
• Needed for LONG-RANGE communication (axon hillock → synapse / NMJ)
• Propagated change affects ENTIRE excitable membrane once initiated

All-or-None Principle

• AP is either generated fully or not at all
• Any depolarizing stimulus ≥ threshold produces IDENTICAL AP amplitude
• Larger stimuli → HIGHER AP FREQUENCY, not larger amplitude

Voltage-Gated $\text{Na}^+$ & $\text{K}^+$ Distribution

• Concentrated on
  • Axolemma of axon, collateral branches & terminals
• Axon hillock has highest density (lowest threshold)

Four Phases of the Action Potential (also Table 12-3)

1. Depolarization to THRESHOLD
   • Large graded depolarization shifts MP to $\approx -60\,\text{mV}$
2. Activation of $\text{Na}^+$ channels → RAPID DEPOLARIZATION
   • $\text{Na}^+$ influx drives MP → $+30\,\text{mV}$ (near $E_{Na}$)
3. Inactivation of $\text{Na}^+$ channels & Activation of $\text{K}^+$ channels
   • $\text{Na}^+$ channels close (inactivate)
   • $\text{K}^+$ channels open → $\text{K}^+$ efflux → REPOLARIZATION begins
4. Closing of $\text{K}^+$ channels
   • Channels begin closing at $-70\,\text{mV}$ but sluggish → HYPERPOLARIZATION ($\approx -90\,\text{mV}$)
   • All VG channels reset → RESTING MP restored

Refractory Periods

• Absolute Refractory Period (≈ $0.4–1.0\,\text{ms}$)
  • From VG $\text{Na}^+$ opening until end of inactivation
  • NO additional AP possible regardless of stimulus size
• Relative Refractory Period
  • VG $\text{Na}^+$ have returned to resting, VG $\text{K}^+$ still open / membrane hyperpolarized
  • AP possible but requires LARGER-THAN-NORMAL depolarization (to offset $\text{K}^+$ efflux & hyperpolarization)

Analogy: Toilet flush

• Resting potential = full tank
• Threshold = push handle hard enough
• Absolute refractory = tank empty cannot flush
• Relative refractory = tank partly refilled, can flush if push strongly

AP Propagation Mechanisms

• Propagation = repeated regeneration of AP, ensuring UNIDIRECTIONAL flow (hillock → terminals) due to refractory states behind wavefront
• Two modes
  1. Continuous Propagation (unmyelinated fibers)
  • Step-by-step depolarization along every piece of membrane
  • Speed ≈ $1\,\text{m/s}$
  • Mexican wave analogy: people stay, the wave moves
  • Steps
    1. Segment 1 depolarizes to $+30\,\text{mV}$
    2. Local current depolarizes segment 2 to threshold
    3. Segment 2 fires; segment 1 repolarizes
    4. Cycle repeats down axon
  1. Saltatory Propagation (myelinated fibers)
  • Myelin (produced by oligodendrocytes / Schwann cells) acts as INSULATOR; VG channels clustered at NODES OF RANVIER
  • Local currents leap node-to-node (internodes insulated)
  • Faster (up to >$100\,\text{m/s}$) & energetically cheaper (fewer ions moved, less $\text{Na}^+/\text{K}^+$-ATPase work)
  • Steps mirror continuous but AP only occurs at nodes (1, 2, 3…)

Orthodromic vs Antidromic Conduction

• Orthodromic = Physiological direction (away from soma for axons)
  • Motor neurons: CNS → muscle
  • Sensory neurons: receptor → CNS
• Antidromic = Opposite direction, possible when AP initiated along axon by external stimulation (e.g., lab electrodes)

Demyelination & Clinical Correlates

• Myelin destruction → slower conduction, AP attenuation (current leaks between nodes)
• Symptoms: sensory loss, motor weakness, paralysis
• Major diseases
  • Multiple Sclerosis (MS) (CNS)
  • Recurrent demyelinating episodes; onset 30-40 yrs
  • Vision loss, fatigue, ataxia, bladder dysfunction
  • Guillain-Barré Syndrome (PNS, autoimmune)
  • Diphtheritic Neuropathy (PNS, bacterial toxin damages Schwann cells)

Comparison: Graded vs Action Potentials (Table 12-3 simplified)

• Graded
  • Depolarize OR hyperpolarize
  • No threshold, amplitude graded with stimulus
  • Passive decay with distance, no refractory period
  • Occur on most membranes (incl. dendrites, soma)
• Action
  • Always depolarizing
  • Require threshold; all-or-none amplitude
  • Self-propagating without decrement
  • Absolute & relative refractory periods
  • Limited to excitable membranes (axons, muscle fibers)

Key Numbers & Equations

• Resting MP (neuron): $\approx -70\,\text{mV}$
• Threshold: $-60 \text{ to } -55\,\text{mV}$
• Peak AP: $\approx +30\,\text{mV}$
• Nernst potential (concept): $E<em>{ion}=\frac{RT}{zF}\ln\frac{[\text{ion}]</em>o}{[\text{ion}]_i}$ governs equilibrium values driving Na/K fluxes
• Propagation velocity ↑ with
  • ↑ axon diameter (↓ internal resistance)
  • Myelination (saltatory conduction)

Practical / Ethical / Real-World Implications

• Nerve conduction velocity studies diagnose demyelinating disorders
• Local anesthetics (e.g., lidocaine) block VG $\text{Na}^+$ channels → prevent AP initiation → analgesia
• Cardiac antiarrhythmics target VG channels to modulate refractoriness
• Neural prosthetics & deep-brain stimulators exploit orthodromic/antidromic activation for therapy

Links to Foundational Principles

• Diffusion & electro-chemical gradients drive ion motion (thermodynamics)
• Cable theory & RC circuits describe passive spread of graded potentials
• Energetics: $\text{Na}^+/\text{K}^+$-ATPase maintains gradients; metabolic compromise → loss of excitability (e.g., stroke)

Study Tips & Mnemonics

• "SAC Me" → Sodium, Acetylcholine, Chemically-gated
• "AIM" for AP phases → Activation (Na), Inactivation (Na) + Activation (K), Meandering back (K closure)
• Toilet analogy for refrain: absolute = empty tank, relative = half-full