Sk4 Ca2+ Activated K+ Channel Is A Critical Player In Cardiac Pacemaker Derived From Human Embryonic Stem Cells
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(2013)
摘要
Proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. Two main mechanisms have been proposed: (i) the "voltage-clock," where the hyperpolarization-activated funny current I-f causes diastolic depolarization that triggers action potential cycling; and (ii) the "Ca2+ clock," where cyclical release of Ca2+ from Ca2+ stores depolarizes the membrane during diastole via activation of the Na+-Ca2+ exchanger. Nonetheless, these mechanisms remain controversial. Here, we used human embryonic stem cell-derived cardiomyocytes (hESC-CMs) to study their autonomous beating mechanisms. Combined current-and voltage-clamp recordings from the same cell showed the so-called "voltage and Ca2+ clock" pacemaker mechanisms to operate in a mutually exclusive fashion in different cell populations, but also to coexist in other cells. Blocking the "voltage or Ca2+ clock" produced a similar depolarization of the maximal diastolic potential (MDP) that culminated by cessation of action potentials, suggesting that they converge to a common pacemaker component. Using patch-clamp recording, real-time PCR, Western blotting, and immunocytochemistry, we identified a previously unrecognized Ca2+-activated intermediate K+ conductance (IKCa, KCa3.1, or SK4) in young and old stage-derived hESC-CMs. IKCa inhibition produced MDP depolarization and pacemaker suppression. By shaping the MDP driving force and exquisitely balancing inward currents during diastolic depolarization, IKCa appears to play a crucial role in human embryonic cardiac automaticity.
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关键词
Ca2+-activated K+ channel SK4, voltage clock, calcium clock, Na+-Ca2+ exchanger, hyperpolarization-activated cyclic nucleotide-gated channel
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