Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 18, Pages E1685-E1694Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221022110
Keywords
Ca2+-activated K+ channel SK4; voltage clock; calcium clock; Na+-Ca2+ exchanger; hyperpolarization-activated cyclic nucleotide-gated channel
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Funding
- Deutsch-Israelische Projektkooperation DIP fund (Deutsche Forschungsgemeinschaft)
- Israel Science Foundation [ISF 488/09, 23/10]
- Ministry of Health [MOH: 3-6273]
- Israel Science Foundation
- Ministry of Health
- Rappaport Family Institute for Research in the Medical Sciences
- Sohnis and Forman Families Stem Cells Center
- Israeli Ministry of Health [2010-3-6266]
- USA-Israeli Binational Research Grant [2009-334]
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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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