SK4 Ca2+ activated K+ channel is a critical player in cardiac pacemaker derived from human embryonic stem cells

David Weisbrod, Asher Peretz, Anna Ziskind, Nataly Menaker, Shimrit Oz, Lili Barad, Sivan Eliyahu, Joseph Itskovitz-Eldor, Nathan Dascal, Daniel Khananshvili, Ofer Binah, Bernard Attali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 If 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.

Original languageEnglish
Pages (from-to)E1685-E1694
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number18
DOIs
StatePublished - 30 Apr 2013

Keywords

  • Ca-activated K channel SK4
  • Calcium clock
  • Hyperpolarization-activated cyclic nucleotide-gated channel
  • Na-Ca exchanger
  • Voltage clock

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