Question 5

Outline the structure of fast cardiac sodium channels and describe in detail how they work.

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College Answer

The expectation for this question was an appropriate description of the fast sodium channel structure included outlining its single alpha and 2 beta sub-units, activation (m) and inactivation (h) gates and sodium selectivity. It was expected that candidates would comment on cycling between the 3 states (resting, open and inactive), corresponding conformational changes to the fast sodium channel, triggers for these changes (voltage or time) and ionic events, including reference to and description of absolute and relative refractory periods. Better candidates were able to relate events to a diagram of a fast action potential, simply drawing a diagram without referencing events at the sodium channel scored few marks. No marks were awarded for description of drug effects on the fast sodium channel. The question specifically relates to fast Na channels, so descriptions of other channels (e.g. ligand gated sodium
channels) did not score marks. Details of the subsequent contraction of cardiac muscle following an action potential was also not part of the question and did not score marks

Discussion

Structure of the voltage-gated sodium channel

  • Heteromeric transmembrane protein (Nav1.5)
  • Made up of a larger (260 kDa) α subunit and two smaller (30 kDa) β-subunits
  • Functionally important elements include:
    • Extremely narrow (4.6 Å2) sodium-selective pore
    • Activating gate (gate)
    • Inactivating gate (h gate)

Three states of activity:

  • Resting state: 
    • m gate is closed and h gate is open; the channel is ready to be opened
  • Open state:
    • Opening is triggered ​​​​​​​by voltage (threshold of -60 to -70 mV)
    • Starts with the opening of the m gate ("helical screw" or "sliding helix" mechanism)
    • Permits flow of sodium ions
    • Stops abruptly within a few milliseconds because of the time-triggered closure of the h gate
  • Inactivated state:
    • Closed h gate; flow of sodium ions is impossible
    • This state ends after 100-140 milliseconds
    • A time-triggered opening of the h gate and closing of the  gate returns the channel to the resting state

Refractory periods:

  • The absolute refractory periodh gate is closed, and no depolarisation is possible
  • The relative refractory period  is the short late period of Phase 3 during which a supranormal stimulus can still produce a depolarisation of the myocyte, which will be of a sub-normal amplitude because only some of the fast sodium channels have entered a resting phase, whereas other have not.
  • The effective refractory period is the period during which the cell either is unable to depolarise, or - if it does depolarise - the amplitude of the depolarisation is so depressed that it could not possibly depolarise any surrounding cells.

References

Yu, Frank H., and William A. Catterall. "Overview of the voltage-gated sodium channel family." Genome biology 4.3 (2003): 1-7.

SB Andavan, G., and R. Lemmens-Gruber. "Voltage-gated sodium channels: mutations, channelopathies and targets." Current medicinal chemistry 18.3 (2011): 377-397.

Jiang, Daohua, et al. "Structure of the cardiac sodium channel." Cell 180.1 (2020): 122-134.

Ulbricht, Werner. "Sodium channel inactivation: molecular determinants and modulation." Physiological reviews 85.4 (2005): 1271-1301.