A physician-validated, board-style question from the Active Transport QBank. Try it, then check the reasoning for every option.
A 21-year-old man presents to a physician with repeated episodes of syncope and dizziness over the last month. On physical examination, his pulse is 64/min while all other vital signs are normal. His 24-hour ECG monitoring suggests a diagnosis of sinus node dysfunction. His detailed genetic evaluation shows that he carries a copy of a mutated gene “X” that codes for an ion channel, which is the most important ion channel underlying the automaticity of the sinoatrial node. This is the first ion channel to be activated immediately after hyperpolarization. Which of the following ion channels does the gene “X” code for?
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A
HCN-channelsCorrect. HCN channels carry the 'funny current' I_f, activate immediately after hyperpolarization, and drive phase 4 spontaneous depolarization of the SA node, making them THE channel of cardiac automaticity.
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B
L-type voltage-dependent calcium channelsIncorrect. L-type Ca²⁺ channels drive phase 0 (the upstroke) of the SA-nodal action potential AFTER threshold is reached — they are not the initiator of automaticity.
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C
Fast delayed rectifier (IKr) voltage-dependent K+ channelsIncorrect. The fast delayed rectifier (I_Kr) repolarizes pacemaker cells during phase 3; it does not initiate diastolic depolarization and is not activated by hyperpolarization.
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D
Stretch-activated cationic channelsIncorrect. Stretch-activated cationic channels modulate firing in response to mechanical load (e.g., atrial stretch) but are not the principal driver of SA-node automaticity.
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E
T-type voltage-dependent calcium channelsIncorrect. T-type Ca²⁺ channels contribute to late phase 4 depolarization in SA-nodal cells but are activated AFTER HCN-mediated I_f has already brought the membrane toward threshold; they are not the first channel activated after hyperpolarization.
↑ Tap an answer to reveal the reasoning
Answer: A. The 'funny current' (I_f) of the sinoatrial node is carried by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels. These channels are unique because, unlike most voltage-gated channels, they OPEN when the membrane hyperpolarizes (around -60 mV at the end of an action potential). HCN channels are mixed Na+/K+ channels that produce an inward depolarizing current, which slowly drives the membrane back toward threshold — generating phase 4 spontaneous depolarization (the diastolic depolarization) of pacemaker cells. This is the molecular basis of SA-nodal automaticity.
The activation sequence in SA-node action potentials: HCN channels first (phase 4 'funny current'), then T-type Ca²⁺ channels open as threshold approaches, then L-type Ca²⁺ channels drive the upstroke (phase 0), and finally delayed-rectifier K+ channels repolarize the cell (phase 3). The faster I_f rises, the steeper phase 4 and the faster the heart rate — which is why beta-adrenergic stimulation (cAMP-mediated enhancement of HCN) speeds the heart and why the HCN blocker ivabradine slows it without affecting contractility.
Mutations in HCN4 (the dominant SA-node isoform) cause familial sinus bradycardia and sick sinus syndrome — exactly the syndrome this patient has.
**Why each option:**
**A.** Correct — HCN channels carry the 'funny current' I_f, activate immediately after hyperpolarization, and drive phase 4 spontaneous depolarization of the SA node, making them THE channel of cardiac automaticity.
**B.** L-type Ca²⁺ channels drive phase 0 (the upstroke) of the SA-nodal action potential AFTER threshold is reached — they are not the initiator of automaticity.
**C.** The fast delayed rectifier (I_Kr) repolarizes pacemaker cells during phase 3; it does not initiate diastolic depolarization and is not activated by hyperpolarization.
**D.** Stretch-activated cationic channels modulate firing in response to mechanical load (e.g., atrial stretch) but are not the principal driver of SA-node automaticity.