Sodium Channel Activation and Inactivation During Phase 0
Sodium channels do not truly activate and inactivate "simultaneously" during phase 0—rather, activation occurs first (within microseconds), followed rapidly by fast inactivation (within 1-2 milliseconds), creating the appearance of simultaneous processes due to their overlapping but sequential time courses.
Sequential Gating Mechanism
The voltage-gated sodium channel undergoes distinct conformational states that occur in rapid succession rather than simultaneously 1, 2:
- Resting state: At negative membrane potentials (around -70 to -90 mV), sodium channels remain closed with the activation gate shut and the inactivation gate open 2
- Activation (Phase 0 upstroke): Upon depolarization reaching threshold, the voltage-sensing domains detect the voltage change and trigger opening of the activation gate within microseconds, allowing massive sodium influx 1, 3
- Fast inactivation onset: Within 1-2 milliseconds after opening, the fast inactivation gate (a hinged lid structure at the cytoplasmic pore opening) swings into position and physically blocks the channel pore from the inside 2, 4
Molecular Basis of the Overlap
The perception of "simultaneous" activation and inactivation stems from the extremely rapid kinetics 5:
- The activation gate opens in microseconds while the inactivation gate begins closing within the first millisecond, creating substantial temporal overlap during the brief phase 0 depolarization 3, 2
- During peak phase 0, some channels are fully open and conducting, while others have already entered the fast-inactivated state, and still others are transitioning between these states 5
- This creates a brief window (typically 1-2 milliseconds) where the sodium current rises rapidly to peak and then declines as progressively more channels enter the inactivated state 2, 4
Structural Transitions
Crystal structure studies reveal the conformational changes underlying these transitions 5:
- Fast inactivation mechanism: A cytoplasmic "hinged lid" formed by the intracellular loop between domains III and IV physically occludes the inner pore opening after the channel activates 4
- Pore domain changes: The S6 helices undergo significant rearrangements, with some collapsing toward the central axis while others move outward, creating asymmetric conformations in the inactivated state 5
- Voltage sensor repositioning: The voltage-sensing domains shift around the pore module during the transition from activated to inactivated states 5
Clinical Relevance
Understanding this sequential process is critical for interpreting channelopathies 2:
- Mutations affecting fast inactivation can prolong sodium current during phase 0, leading to conditions like long QT syndrome type 3 where delayed inactivation causes persistent inward sodium current 6
- Beta-subunit interactions can modify both the voltage dependence of activation and inactivation, as well as the kinetics of these transitions 6
- Drug effects: Many antiarrhythmic agents and local anesthetics preferentially bind to inactivated channel states, exploiting the brief window when channels transition from open to inactivated 5
Common Pitfall to Avoid
Do not confuse fast inactivation (millisecond timescale, occurring during and immediately after phase 0) with slow inactivation (seconds timescale, occurring with repetitive stimulation), as these involve different molecular mechanisms and different structural regions of the channel 2, 4. Fast inactivation involves the cytoplasmic hinged lid mechanism, while slow inactivation involves conformational changes deeper within the pore structure itself 4.