Neuron Excitability (3)
Potassium Leakage at the Soma (Cell Body)
The soma (cell body) contains numerous potassium (K⁺) leakage channels.
Constant K⁺ efflux continually makes the interior of the cell less positive (more negative).
Sodium (Na⁺) leakage channels also exist but help graded depolarizations rather than hinder them because Na⁺ influx adds extra positive charge.
Consequence for graded potentials (GP):
A depolarizing GP triggered by ligand-, mechanical-, or other stimulus spreads across the soma.
As it spreads, part of the positive charge leaks out through K⁺ channels, diminishing the amplitude of the GP.
Therefore, the initial GP must be large enough to compensate for this ionic loss and still reach the axon hillock at -55\;\text{mV} (threshold).
Threshold, Axon Hillock, Neurotransmitter Release
Axon hillock = trigger zone packed with voltage-gated Na⁺ channels.
If the local voltage here climbs to -55\;\text{mV}:
First Na⁺ channel opens ➔ domino effect ➔ full action potential (AP).
AP travels entire axon ➔ Ca²⁺ influx at terminals ➔ neurotransmitter (NT) exocytosis.
Failure to reach threshold = no AP, no NT release (all-or-none principle).
Potassium Leakage Along the Axon & Need for Myelination
Axons also possess K⁺ leak channels that could slow or dampen the propagating AP.
Evolutionary solution: myelination—lipid insulation that blocks ion flow through most of the axonal membrane.
Myelination Mechanics
CNS: oligodendrocytes ; PNS: Schwann cells.
Each glial cell wraps a lipid membrane layer(s) around the axon → myelin sheath (purple in diagram).
Immediate effects of the sheath:
Blocks all ion movement (no K⁺ leak, no Na⁺ entry) under the myelin.
Restricts ion permeability to the exposed gaps—the Nodes of Ranvier.
Nodes of Ranvier & Saltatory Conduction
Nodes contain very high densities of voltage-gated Na⁺ channels (some K⁺ leak channels may exist but are outnumbered).
The impulse effectively “jumps” node-to-node instead of inching micrometer by micrometer.
Spanish analogy: saltar = “to jump” → saltatory conduction.
Results:
Dramatically ↑ conduction velocity.
↓ total surface area that needs Na⁺/K⁺ pumping ➔ energy savings.
Energetic Benefit—Fewer Na⁺/K⁺-ATPases Required
Each influx of Na⁺ & efflux of K⁺ during an AP must be reversed by the Na⁺/K⁺ pump (Na⁺/K⁺-ATPase).
Myelination localizes ion flux to nodes → fewer pumps needed → less ATP consumed; neuron can divert ATP to other metabolic tasks.
Graded Potentials vs. Action Potentials
Location
GP: dendrites & soma.
AP: axon & terminals only.
Electrical effect
GP: can depolarize or hyperpolarize.
AP: always a stereotyped depolarization–repolarization sequence.
Amplitude principle
GP: variable, can undergo summation (temporal or spatial) if stimuli occur before previous GP fades.
AP: all-or-none; once threshold is hit, amplitude is fixed.
Clinical / Pharmacological Connections
Multiple Sclerosis (MS)
Autoimmune demyelination ➔ slowed or blocked APs ➔ motor & sensory deficits.
Local anesthetics (e.g., lidocaine)
Reversibly bind voltage-gated Na⁺ channels ➔ stop APs in nociceptive (pain) neurons ➔ loss of pain sensation during minor procedures.
Resting Membrane Potential (RMP) & Leakage Channels
Typical neuron RMP ≈ -70\;\text{mV}.
Causes:
More K⁺ leak channels than Na⁺ leak channels.
K⁺ chemical gradient drives efflux (leaving positive charge).
Intracellular anions (proteins, phosphates) add negativity.
Na⁺ has both chemical & electrical incentive to enter but has fewer leak pathways.
Potassium Imbalances
Hypokalemia (↓[K⁺]ₑ)
Larger outward K⁺ gradient ➔ ↑ K⁺ efflux.
RMP becomes more negative (e.g., -95\;\text{mV}).
Threshold now farther away (ΔV ≈ 35 mV vs 15 mV) ➔ neuron less excitable.
Causes: low dietary K⁺, excessive fluid intake, certain diuretics.
Hyperkalemia (↑[K⁺]ₑ)
Reduced outward gradient ➔ ↓ K⁺ efflux.
RMP becomes less negative (e.g., -60\;\text{mV}).
Threshold closer (ΔV ≈ 5 mV) ➔ neuron more excitable.
Both hypo- and hyper- states are dangerous; body relies on renal & hormonal systems to maintain K⁺ homeostasis.
Neurotransmitter Control of Excitability
GABA (γ-aminobutyric acid)
Opens Cl⁻ channels (Cl⁻ higher outside cell).
Cl⁻ influx → hyperpolarization → inhibitory.
Many inhaled anesthetics enhance GABAergic signaling to suppress consciousness & pain.
Glutamate & Aspartate
Excitatory amino-acid NTs; generally open cation channels (Na⁺/Ca²⁺) → depolarization.
GABA-induced hyperpolarization is a physiological counterpart to the pathological hyper-/hypokalemia scenarios.
Action Potential Waveform & Refractory Periods
Standard diagram: Rest -70\;\text{mV} → Threshold -55\;\text{mV} → Rapid depolarization → Repolarization → Possible hyperpolarization → Return to rest.
Absolute Refractory Period (ARP)
From threshold upstroke until full repolarization.
Impossible to fire a second AP—voltage-gated Na⁺ channels are inactivated.
Relative Refractory Period (RRP)
Coincides with hyperpolarization (undershoot).
Possible to fire again, but requires larger GP because membrane is further from threshold.
Molecular Basis—Voltage-Gated Na⁺ Channel States
Channel has two gates:
Activation gate (extracellular side)
Inactivation gate (intracellular side)
Resting (closed, but capable)
Activation gate closed; inactivation gate open.
Open (activated)
Depolarization moves voltage sensor ➔ activation gate swings open → Na⁺ influx.
Inactivated
Almost immediately, inactivation gate plugs channel even though activation gate remains open.
Channel cannot reopen until membrane repolarizes, resetting both gates → basis of ARP.
Broader Homeostatic Perspective
Similar hypo-/hyper- disorders exist for Na⁺ (hyponatremia / hypernatremia) and Ca²⁺ (hypocalcemia / hypercalcemia).
Endocrine, renal, and respiratory systems collaborate to maintain extracellular ion concentrations, fluid volume, and pH → ensures neurons & muscles operate within safe electrical limits.
Connections to Previous Lectures
Reiterates importance of graded potentials at dendrites/soma and the Na⁺/K⁺-ATPase cycle mentioned earlier.
Builds on earlier discussion of membrane transport proteins and glial cell types.
Links excitability concepts to clinical examples (MS, anesthetics) foreshadowing later lectures on neuropharmacology and neuromuscular physiology.
Ethical & Practical Implications
Understanding myelination has guided therapeutic strategies in demyelinating diseases.
Local anesthetic usage requires balancing pain control with the protective value of nociception.
Manipulation of GABAergic vs glutamatergic signaling underlies anesthesia, epilepsy treatment, and psychiatric medications—necessitating ethical frameworks for CNS drug development.