In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 18 ( 2013-04-30)
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 I f causes diastolic depolarization that triggers action potential cycling; and ( ii ) the “Ca 2+ clock,” where cyclical release of Ca 2+ from Ca 2+ stores depolarizes the membrane during diastole via activation of the Na + –Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ -activated intermediate K + conductance (IK Ca , KCa3.1, or SK4) in young and old stage-derived hESC-CMs. IK Ca inhibition produced MDP depolarization and pacemaker suppression. By shaping the MDP driving force and exquisitely balancing inward currents during diastolic depolarization, IK Ca appears to play a crucial role in human embryonic cardiac automaticity.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1221022110
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2013
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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