Learning Objectives
- Describe the structure and functional states of voltage-gated Na⁺ and K⁺ channels.
- Explain how voltage-gated ion channels generate the phases of the action potential.
- Discuss how hyperkalemia alters neuronal excitability by affecting Na⁺ channel states.
- Recognize pharmacologic and toxicologic agents that alter Na⁺ channel behavior.
Voltage-Gated Ion Channels
Voltage-gated ion channels are essential for generating the action potential. Their opening and closing in response to membrane voltage determine when a cell depolarizes, repolarizes, or becomes refractory.
Clinical Correlate: Hyperkalemia and Neuronal Excitability
Hyperkalemia depolarizes the resting membrane potential.
- Acute effect: Neuron becomes more excitable because Em is closer to the threshold.
- Chronic effect: Persistent depolarization causes many fast Na⁺ channels to enter the inactivated state.
- Because the membrane does not repolarize back to normal, the channels cannot return to the closed (inactive) state.
- Result: Reduced number of available Na⁺ channels → decreased excitability, increasing risk of muscle weakness and conduction abnormalities.
Voltage-Gated (Fast) Na⁺ Channels
These channels generate the rapid depolarization (upstroke) of the action potential.
Gates and States
A fast Na⁺ channel has 2 gates and 3 conformational states:
1. Closed State
- Activation gate (m-gate): closed
- Inactivation gate (h-gate): open
- Na⁺ conductance is low.
- This is the resting, ready-to-open state.
2. Open State
Triggered by depolarization.
- Both m-gate and h-gate are open.
- Large Na⁺ influx → further depolarization, activating more Na⁺ channels.
- This positive-feedback loop drives the upstroke of the action potential.
Each Na⁺ channel has its own threshold, but many open together when the membrane reaches the global threshold value.
3. Inactivated State
- m-gate: open
- h-gate: closed
- Occurs shortly after opening, usually as the membrane becomes positive.
- Cannot reopen directly.
- Only returns to the closed state after the membrane repolarizes.
Conditions that prevent repolarization (e.g., hyperkalemia) keep channels locked in the inactivated state, reducing excitability.
Additional Notes
- High extracellular Ca²⁺ reduces excitability by blocking fast Na⁺ channels.
- Low extracellular Ca²⁺ increases excitability by lowering the threshold.
Voltage-Gated K⁺ Channels
These channels mediate repolarization of the action potential.
Key Features
- Closed at rest
- Open during depolarization, but with slow kinetics compared to fast Na⁺ channels
- Their opening allows K⁺ efflux, bringing the membrane potential back to negative
- Responsible for:
- Repolarization
- After-hyperpolarization (when they remain open briefly)
Bridge to Pharmacology
Agents that Block Fast Na⁺ Channels
- Tetrodotoxin (TTX) – Pufferfish
- Saxitoxin (STX) – Algae, Shellfish
- Local anesthetics (e.g., lidocaine, bupivacaine)
Effect: Prevent Na⁺ influx → block action potential → loss of sensation or paralysis.
Agents that Prevent Na⁺ Channel Inactivation
- Ciguatoxin (CTX) – reef fish
- Batrachotoxin (BTX) – poison-dart frogs
Effect: Keep channels persistently open → prolonged depolarization → paralysis, arrhythmias.
