Step 1 topics → Neurology and Special Senses → Resting Membrane Potential and Action Potential

Resting Membrane Potential and Action Potential

USMLE Step 1 trap: Confuses repolarization mechanism (voltage-gated K+ channels) with the Na+/K+-ATPase pump. Repolarization is caused by opening of voltage-gated K+ channels (K+ efflux), not the Na+/K+-ATPase pump, which restores resting ion gradients on a slower timescale.

Resting membrane potential and action potentials are foundational neuroscience concepts that show up repeatedly on USMLE Step 1 — both as direct recall questions and as the underlying mechanism behind drug effects, toxins, and clinical scenarios. The resting membrane potential sits around -70 mV, maintained primarily by K+ leak channels and the Na+/K+-ATPase. Action potentials follow a stereotyped sequence: depolarization via voltage-gated Na+ channels, rapid inactivation of those channels, repolarization via voltage-gated K+ channels, and a brief hyperpolarization before returning to rest. Saltatory conduction in myelinated axons accelerates this whole process by jumping between nodes of Ranvier.

The exam tests this at multiple levels. Simple questions ask you to identify which ion or channel is responsible for a given phase. Harder questions embed this in a clinical or toxicology context — local anesthetics block Na+ channels, tetrodotoxin does the same, hyperkalemia shifts the resting potential, and demyelinating diseases disrupt saltatory conduction. You need to understand mechanism, not just memorize labels.

What trips students up most is conflating different players that happen to involve the same ions. The Na+/K+-ATPase and voltage-gated K+ channels both involve K+, but they operate on completely different timescales and serve different functions. Similarly, students mix up absolute and relative refractory periods, not realizing the distinction comes down to Na+ channel gating state. USMLE Step 1 loves to test exactly these fine distinctions, so get the mechanism cold before moving on.

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Common misconceptions

Common mistake
Wrong: Repolarization during the action potential is caused by the Na+/K+-ATPase pump.
Right: Repolarization is caused by opening of voltage-gated K+ channels (K+ efflux), not the Na+/K+-ATPase pump, which restores resting ion gradients on a slower timescale.
The Na+/K+-ATPase is a slow, metabolically driven pump that gradually restores ion gradients after many action potentials — it is not fast enough to repolarize the membrane during a single action potential. Repolarization happens in milliseconds and is driven by voltage-gated K+ channels opening and allowing K+ to rush out of the cell, pulling the membrane potential back toward the K+ equilibrium potential. Think of the pump as housekeeping between rounds, not as the mechanism that ends each round.
Common mistake
Wrong: Both the absolute and relative refractory periods prevent any action potential from firing.
Right: During the absolute refractory period no stimulus can trigger an AP (Na+ channels inactivated); during the relative refractory period a stronger-than-normal stimulus can trigger an AP (some K+ channels still open, membrane hyperpolarized).
During the absolute refractory period, voltage-gated Na+ channels are inactivated — they are physically blocked and cannot reopen no matter how strong the stimulus, so no action potential is possible. During the relative refractory period, Na+ channels have recovered but voltage-gated K+ channels are still partially open, making the membrane hyperpolarized and harder to depolarize — a stronger-than-normal stimulus can overcome this and fire an AP. The key distinction is whether firing is physically impossible (absolute) versus just harder (relative).
Common mistake
Wrong: The resting membrane potential is determined primarily by Na+ permeability.
Right: The resting membrane potential is determined primarily by K+ permeability through leak channels, because the membrane is far more permeable to K+ at rest than to Na+.
At rest, the membrane is far more permeable to K+ than to Na+ because K+ leak channels are open while voltage-gated Na+ channels are closed. Because K+ can move freely across the membrane, the resting potential is pulled close to the K+ equilibrium potential (approximately -90 mV), with Na+ contributing only a small depolarizing offset. If Na+ dominated, the resting potential would be near +60 mV — the fact that neurons sit at -70 mV tells you K+ is in charge.
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What the exam tests

  1. Identify which ion and which channels are primarily responsible for setting the resting membrane potential — and explain why K+, not Na+, dominates.
  2. Trace the sequence of Na+ channel gating states (closed → open → inactivated → closed) through each phase of the action potential, including what triggers each transition.
  3. Distinguish between the absolute and relative refractory periods mechanistically: what is happening to Na+ and K+ channels in each period, and what that means for the neuron's ability to fire another action potential.

Can you avoid these mistakes?

A toxin selectively blocks voltage-gated K+ channels without affecting Na+ channels. What happens to the repolarization phase of the action potential, and why?
A neuron is in its absolute refractory period. A researcher applies a stimulus twice the normal threshold intensity. Does an action potential fire? Explain using Na+ channel gating states.
If you increased extracellular K+ concentration (as in hyperkalemia), would you expect the resting membrane potential to become more positive or more negative? Walk through the reasoning using the concept of K+ equilibrium potential.
A toxicologist explains that local anesthetics preferentially bind voltage-gated Na+ channels in a specific gating state, which is why they work better on rapidly firing neurons. During which phase of the action potential are Na+ channels in the inactivated state, what structural feature of the channel is responsible, and how does this explain why local anesthetics have use-dependent block?

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